JPH04283553A - Hiv protease inhibitor having polyether substituent - Google Patents

Abstract

PURPOSE: To provide a new polyether deriv. or its pharmaceutically acceptable salt which inhibits a protease coded by human immunodeficiency virus.

CONSTITUTION: This compd. is expressed by formula I, and the inhibitor contains the compd. or its pharmaceutically acceptable salt. In formula I, A is H, R¹-C(=O)-, (wherein R¹ is H, alkyl, aryl or 5- to 6-membered heterocyclic group), R¹SO₂, etc.; G is expressed by formula II; B is independent and is not present or expressed by formula, IV. In formula II, Z is O, S, NH; R_a ⁹, R_b ⁹ are expressed by formula III (wherein (q) is 0 to 5; R¹⁰ is H, OH, alkyl; R¹¹ is aryl, etc.); Q is -CH(OH)CH₂-, -CH₂NH-, etc.). In formula IV, R²⁰ is a hydrophobic group, J is YR¹⁶ (wherein Y is O, NH; R¹⁶ is H, alkyl, etc.). The compd. is., for example, N-[2-(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)- hydroxy-2(R)-[4-(1,4,7-trioxaoctyl)phenyl]methyl-6-phenylhexaneamide.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

[0001] The present invention relates to human immunodeficiency virus (HIV).
Compounds that inhibit proteases encoded by. This compound or its pharmaceutically usable salt is HI
It is useful in the prevention of V infection, the treatment of HIV infection and the resulting acquired immunodeficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and methods of using the compounds and other agents for the treatment of viral infections due to AIDS and HIV.

[0002] Retroviruses named human immunodeficiency virus (HIV) are the causative agents of complex diseases including progressive destruction of the immune system (acquired immunodeficiency syndrome; AIDS) and degeneration of the central and peripheral nervous systems. This virus used to be in LA
V, HTLV-III or ARV. A common feature of retroviral replication is extensive post-translational processing of polyprotein precursors by virus-encoded proteases to generate mature viral proteins necessary for virus assembly and function. Blockage of this processing appears to prevent normal production of infectious virus. For example, Crawford, S. et al., J. Virol. Volume 53, No. 899
Page 1985 (Crawford. S. et. a
l. , J. Virol. 53,899,1985
) demonstrate that genetic deletion mutations of the protease in murine leukemia virus that prevent processing of structural protein precursors result in non-infectious virus particles. Non-processed structural proteins have also been observed in clones of non-infectious HIV strains isolated from human patients. These results suggest that inhibition of HIV protease represents a viable method for treating AIDS and preventing or treating HIV infection.

Nucleotide sequencing of HIV shows the presence of the pol gene in one open reading frame [Ratner, L. et al., Nature, Vol. 313, No. 2]
77, 1985 (Ratner, L. et.
al. Nature, 313, 277 (1985))
]. Amino acid sequence homology shows evidence that the pol sequence encodes reverse transcriptase, endonuclease, and HIV protease [To, H. et al. Etc.
MBO J. Volume 4, page 1267, 1985 (To
h, H. et. al. EMBOJ. 4, 1
267 (1985); Power M. D. etc., science,
Volume 231, page 1567, 1986 (Power,
M. D. et. al. Science, 23
1, 1567 (1986); Pearl, L. H. (Pea
rl L. H. ) et al., Nature, Volume 329,
No. 351, 1987]. Applicants demonstrate that the compounds of the invention are inhibitors of HIV protease. Individual advantages of the compounds of the invention are their potency and bioavailability. Polyether substituents enhance solubility, another advantage of the invention.

Compounds of Formula I are disclosed as defined herein. These compounds, either as compounds, pharmaceutically acceptable salts, or components of pharmaceutical compositions, with or without other antiviral agents, immunomodulators, antibiotics, or vaccines, are effective agents of HIV protease. It is useful in inhibiting HIV infection, preventing HIV infection, treating HIV infection, and treating AIDS. Also, how to treat AIDS, HIV
Also disclosed are methods for preventing infection and treating HIV infection.

[0005]
Abbreviation name
Activator HBT (HOBT or HOBt)
1-hydroxybenzotriazole hydrate

Condensing agent EDC
1-ethyl-3-(3-
dimethylaminopropyl
) Carbodiimide
Deprotonating agent LD
A
Lithium diisopropylamide

Other reagents Bu4N+ F −
Tetrabutylammonium fluoride DME
dimethoxyethane DMF
Dimethylformamide MCPBA
m-chloroperbenzoic acid TBAF
Tetrabutylammonium fluoride TBDMSCI
t-butyldimethylsilyl chloride

[0006]
The present invention relates to the use of compounds of formula I, combinations thereof or pharmaceutically usable salts thereof in the inhibition of HIV protease, the prevention or treatment of HIV infection and the treatment of consequent acquired immunodeficiency syndrome (AIDS). Regarding usage.

The compound of formula I is defined as follows. A-G-B-B-J
I [wherein A is 1) hydrogen 2) R1-C(=O)- {R1 is a) unsubstituted or i) C1-4 alkyl, ii) hydroxy, iii) carboxy, iv) halo (halo is F , Cl, Br or I), v) amino, vi) C1-3 alkoxycarbonyl, vii
) C1-3 alkoxy, viii) -CONR2R3 (R2 and R3 are the same or different, hydrogen, C1-5 alkyl or C1-
5 alkoxyalkyl or joined together directly to form a 5- to 7-membered heterocycle or together with the nitrogen to which they are attached via a heteroatom selected from N, O and S to form a 6-membered heterocycle ), ix) -NR2R3
, x) -N(R)-D-R4 (R is hydrogen or C1-4
is alkyl, and D is -C(=O)-, -C(=S
)-, -S(=O)2-, -C(=NR)-, where R4 is NHR, C1-3 alkyl, C1-4
alkoxy or NR2R3), xi) C3-7 cycloalkyl or C6-10
Aryl, xii) unsubstituted or -OH, N
5- or 6-membered heterocycle substituted with HR or C1-4 alkyl, or xiii) unsubstituted or (a) halo, (b) hydroxy, (c) C1-3 alkoxy, (d) C1-3 alkyl, ( e) -NR2 (R is defined above), (f)
-C(=O)OR, (g) -C(=O)NR2, (h) -SO2NR2, (i) -CH2NR2, (j) -N(R)-C(=O)-R or (k ) −
Aryl with 6 to 10 carbon atoms substituted with one or more of N(R)-SO2R, xiv) X[(CH2)mO]nR (X=CH
2, NR, O, S, SO or SO2, n=1-6,
m is 1 to 3, each within repeating unit n, and R
C1− is substituted with one or more of
6 alkyl b) unsubstituted or i) C1-4 alkyl, ii) C1-3 alkoxy, iii) hydroxy or iv) halo, v) -NR2, vi) -C(=O)OR, vii) -C( =O)NR2, viii) -SO2NR2, ix) -CH2NR2, x) -NRCOR or xi) -NRSO2R, xii) X[(CH2)mO]nR(X=CH2
, NR, O, S, SO or SO2, n=1-6, m is 1-3 but each within repeating unit n, R is defined above)xiii) CH2X[(CH2)
mO] nR aryl having 6 to 10 carbon atoms substituted with one or more c) is a 5- or 6-membered heterocycle} 3) R1-SO2-, 4) R1N (R5) SO2 (R5 is H or C1-5
alkyl or directly bonded together with R1
5) R1N(R5)C(=O) - 6) R1-S-C(=O)- 7) R6C(R7)(R8)-O-C(=O)-(R6
, R7 and R8 are independently a) H, b) unsubstituted or i) halo, ii) OH, iii) aryl SO2-, iv) -O-[(CH2)mO]n-R,
c) unsubstituted or i) C1-4 alkyl, ii) C1-3 alkoxy, iii) halo, iv) nitro, v) acetoxy, vi) dimethylaminocarbonyl, vii )
phenyl;
-10 cycloalkyl, which can form a monocyclic, bicyclic or tricyclic ring which can be substituted with C1-4 alkyl. f) is a 5- to 7-membered heterocycle). G is

embedded image {Z is O, S or NH. R9a or R9b is independently 1)

embedded image Or 2) C1-4 alkylene-R11. q is 0-5 and R10 is independently a) hydrogen, b) hydroxy or c) C1-4 alkyl. However, R9a or R9b is always substituted with R12. R11 is a) C6-C10 aryl unsubstituted or substituted with one or more of R12 and optionally i) halo, ii) C1-4 alkyl, iii) C1-3 alkoxy, b)
Containing 1 to 3 heteroatoms selected from N, O, S, substituted with R12 and optionally one or more of i) halo, ii) C1-4 alkyl, iii) C1-3 alkoxy. c) unsubstituted or R12 and optionally i)
Hydroxy, ii) C1-4 alkyl, iii) -NH2, -NHR, -NR2,
iv) -NHC(=NH)H, v) -NHC(=NH)NH2, vi) -COOH, vii) -C(=O)OR, viii) SR, S(O)R and S(O2)R
, ix) -SO2NHR, x) C1-4 alkylsulfonylamino or arylsulfonylamino, xi) -CONHR, xii) -NHC(=O)R, xiii) -OR, xiv) arylC1-3 alkoxy or xv)
aryl, C1-6 alkyl or C1-6 substituted with one or more of
6 alkenyl, d) unsubstituted or R12 and optionally i)
Hydroxy, ii) C1-4 alkyl, iii) -NH2, -NHR, -NR2,
iv) -NHC(=NH)H, v) -NHC(=NH)NH2, vi) -COOH, vii) -C(=O)OR, viii) SR, S(O)R and S(O2)R
, ix) -SO2NHR, x) C1-4 alkylsulfonylamino or arylsulfonylamino, xi) -CONHR, xii) -NHC(=O)R, C3-7 cycloalkyl substituted with one or more of the following. R12 is a)X[((CH2)mO)n]R13(X=
CH2, NR, O, S, SO or SO2, n=1~
6, m is 1 to 3, but each is within the repeating unit n, and R13 is i) H or C1-4 alkyl, ii) C(=O)R1, iii) C(=O)X1[(CH2 )mO]nR(
X1 is NR or O) iv) P(=O)(
OM)2 (M is a mono- or divalent metal ion) v) C(=O)OR1, vi) R1R5NC(=O)) b) CH2X[((CH2)mO)n]R13 It is. R15 is -H, -C(=O)H, -C1-4 alkyl or -COOR. Q is

[Chemical formula 9] (R15 is defined above). X11 is O, S or NH. W is 1) OH, 2) NH2, 3) OR or 4) NHR. }. B does not exist independently or

embedded image (R20 is a hydrophobic group, a) -CH(CH3)2, b) -CH(CH3)(CH2CH3) or c)-
phenyl). J is 1) YR16 {Y is O or NH. R16 is a) H, b) unsubstituted or i) -NR2, ii) -OR, iii) -NHSO2C1-4 alkyl, iv)
-NHSO2aryl or -NHSO2 (dialkylaminoaryl), v) -CH2OR, vi) -C1-4 alkyl, vii) -C(=O)OR, viii) -C(=O)NR2, ix) -NHC( =NH)NR2 or -NHC
(=N(CN))NR2,x) -NHC(=O)
R, xi) -N(CH2CH2OH)SO2CH3,
xii) -NHC(=O)OCH2Ph, xiii
) -NR3+ A - (A- is a counterion)
xiv) -NR17R18 (R17 and R18 are the same or different, are C1-5 alkyl and directly bonded together contain up to one heteroatom selected from -O-, -S- or -NR-) xv) aryl, xvi) -CHO, xvii) -OP(O)(ORx)2 (Rx is H or aryl) or xviii) amine or quaternary amine or -O-
[(CH2)mO]n-R or -OP(O)(ORx
)2 substituted with one or more -OC(=O)C1-
C1-6 alkyl substituted with one or more of 4 alkyl, c)-[
(CH2)mO]nCH3 or -[(CH2)mO]
nH}2) N(R16)2, 3)-NR17R18 (R17 and R18 are defined above) or 4)

embedded image {Y, R16 and q are defined above. R19 is a
) hydrogen, b) unsubstituted or i) halo, ii) -OR (R is H or C1-4 alkyl), iii) -C(=O)OR, iv) -C(=O)NR2, v) -CH2NR2, vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) phenyl, xi) -CF3, xii) -N(R)-SO2R , xiii) -C1-4 alkyl-NR2 , xiv
) -OP(O)(ORx)2 (Rx is H or aryl) or xv) amine or quaternary amine or -OP(O
)(ORx)2 substituted with one or more -OC(=O
) aryl substituted with one or more C1-4 alkyls, c) saturated or unsaturated and the ring is unsubstituted, or
i) halo, ii) -OR (R is H, C1-4 alkyl or C1-4 alkenyl), iii) -C(=O)OR, iv) -C(=O)NR2, v) -CH2NR2 , vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) phenyl, xi) -CF3, xii) -N(R)-SO2R, xiii) phenyl C1-4 alkyl, xiv)
-OP(O)(ORx)2 (Rx is H or aryl), xv) amine or quaternary amine or -
OP(O)(ORx)2 or -O[(CH2)mO]
-OC(=O)C1- substituted with one or more of n-R
4 alkyl, xvi) -OC(=O)-O-[(CH2)mO]
5- to 7-membered heterocycle substituted with one or more of n-R or 7- to
10-membered bicyclic heterocycle or xvii) When sulfur or nitrogen is incorporated into the heterocycle, the oxidized forms of S or N, ie sulfoxide, benzothiopyranyl sulfone, sulfone or N-oxide are also included. d) saturated or unsaturated and unsubstituted on the carbocycle or i) halo, ii) -OR (R is H or C1-4 alkyl), iii) -C(=O)OR, iv) -C(=O)NR2, v) -CH2NR2, vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) Phenyl, xi) -CF3, xii ) -N(R)SO2R, xiii) -OP(O)(ORx)2 (Rx is H or aryl), xiv) amine or quaternary amine, -OP(O)(ORx)2 or -O −[(C
-OC(=
O)-C1-4 alkyl or xv) -OC(=O)-O-[(CH2)
It is a 5- to 7-membered carbocycle or a 7- to 10-membered bicyclic carbocycle substituted with one or more of mO]nR. } is. ] or a pharmaceutically usable salt thereof.

In one embodiment of the invention, A is R1C(
=O)- or R6C(R7)(R8)-O-C(=
O)-, and G is

[Chemical formula 12] The second embodiment is further limited, B is absent or present and Q is C(OH)H-CH2. A third embodiment is further limited, B is absent and J is N
HR19 and R19 is a substituted 7- to 10-membered bicyclic carbocycle or heterocycle that is saturated or unsaturated. The fourth embodiment is further limited to J which is either unsubstituted or substituted as indanyl, benzo[C]thiopyranyl-2,2-dioxide or cyclopentyl.

The novel compounds of the present invention include, but are not limited to, the following: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-
dimethylethyloxycarbonylamino)-4(S)-
Hydroxy-2(R)-(4-(1,4,7-trioxaoctyl)phenyl)methyl-6-phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5 (S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethoxy)phenylmethylhexanamide, N-(2(R )-Hydroxy-
1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethyl)phenylmethyl Hexanamide, N-(2(R)-
Hydroxy-1(S)-indanyl)-5(S)-(1
,1-dimethylethoxycarbonyl)amino-4(S)
-Hydroxy-6-phenyl-2(R)-4-(3-hydroxypropyl)phenylmethylhexanamide, N
-(2(R)-hydroxy-1(S)-indanyl)-
5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)
-4-(3-(2-methoxyethoxy)methoxypropyl)phenylmethylhexanamide, [5(S)-(1
,1-dimethylethoxycarbonylamino)-4(S)
-Hydroxy-6-phenyl-2(R)-4-(2-hydroxyethoxy)phenylmethylhexanoyl]-valine-N-3,6,9,12-tetraoxatridecylamide, [5(S)- (1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethoxy)phenylmethylhexanoyl]-valine-N-3,6,9 ,12
, 15-pentaoxapentadecylamide, N-(2(
R)-hydroxy-1(S)-indanyl)-5(S)
-(1,1-dimethylethoxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-[4-
(1,4,7,10-tetraoxaundecyl)phenyl]methylhexanamide, N-(2(R)-(hydroxy-1(S)-indanyl)-5(S)-(1,1-
dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(methoxyethoxyethoxy)phenyl]methylhexanamide, N
-(2(R)-hydroxy-1(S)-indanyl)-
5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)
-[4-(methoxyethoxy)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4( S)-hydroxy-6-phenyl-2(R)-[4-(1,4,7,10,13-pentaoxatetradecyl)phenyl]methylhexanamide, N-(4-(3,4-dihydro -(1H)-2-benzo[C]thiopyranyl-2,2-dioxide))-5
(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-
4(3-hydroxypropyl)phenylmethylhexanamide,

N-(2(R)-hydroxy-1(S)-
indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(
R)-(5-thia-7-hydroxy-2(E)-hepten-1-yl)-6-phenylhexanamide, N-(
2(R)-hydroxy-1(S)-indanyl)-5(
S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(5-thia-
8-hydroxy-2(E)-octen-1-yl)-6
-Phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R )-4-(4-hydroxy-2-thiabut-1-yl)phenylmethyl-6-phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-( 1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R
)-(5,8,11,14,17-pentaoxaoctadec-2(E)-en-1-yl)-6-phenylhexanamide, N-(2(R)-hydroxy-1(S )−
indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(
R)-4-(2-hydroxyethylsulfonylmethyl)
Phenylmethyl-6-phenylhexanamide, N-(
2(R)-hydroxy-1(S)-indanyl)-5(
S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-4-(2,5
,8,11,14-pentaoxapentadec-1-yl)phenylmethyl-6-phenylhexanamide, N-
(2(R)-hydroxy-1(S)-indanyl)-5
(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2
-(hydroxy)ethoxy)phenyl)methyl-6-cyclohexyl-hexanamide, N-(4-fluoro-
2(R)-hydroxy-1(S)-indanyl)-5(
S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2-
hydroxyethyloxy)phenylmethyl-6-phenylhexanamide, N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)- hydroxy-6-phenyl-2(R)-[4-(2-hydroxyethoxy)phenyl]methylhexanamide,

N-(1-hydroxy-3-methyl-2-
cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-
Phenyl-2(R)-[4-(2-methoxyethoxy)
phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,
1-dimethylethoxycarbonylamino)-4(S)-
Hydroxy-6-phenyl-2(R)-[4-(1,4
,6,9,12,15,18-heptaoxa-5-oxo-nonadecyl)phenyl]methylhexanamide, N
-(2(R)-hydroxy-1(S)-indanyl)-
5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)
-[4-(6-aza-1,4,9,12,15,18-
Hexaoxa-5-oxo-nonadecyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1
(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-
6-phenyl-2(R)-[4-(2-phosphoryloxyethoxy)phenyl]methylhexanamide or N-
(2(R)-hydroxy-1(S)-indanyl)-5
(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-
[4-(2-phosphoryloxypropyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1
(S)-indanyl)-5(S)-(3-oxabutyloxycarbonylamino)-4(S)-hydroxy-2
(R)-(4-(2-hydroxy)-ethoxyphenyl)methyl-6-phenylhexanamide, N-(2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(3,6-dioxaheptyloxycarbonylamino)
-4(S)-hydroxy-2(R)-((4-(2-hydroxy)ethoxy)phenyl)methyl-6-phenylhexanamide, N-(2(R)-hydroxy-1(S)
)-indanyl)-5(S)-(3,6,9,12-tetraoxa-tridecyloxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-[4-
(1,4,7-trioxaoctyl)phenyl]methylhexanamide,

N-(2(R)-hydroxy-1(S)-
indanyl)-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-6
-Phenyl-2(R)-[4-(1,4-dioxapentyl)phenyl]methylhexanamide, N-(2(R)
)-hydroxy-1(S)-indanyl)-5(S)-
(3,6-dioxaheptyloxycarbonylamino)
-4(S)-hydroxy-6-phenyl-2(R)-[
4-(1,4,7-trioxaoctyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1
(S)-indanyl)-5(S)-(3,6,9-trioxadecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4 ，
7-trioxaoctyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3,6,9,12-tetraoxa-tridecyloxycarbonyl) amino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4-
dioxapentyl) phenyl] methylhexanamide,
N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(2-(2-methoxyethoxy)ethoxycarbonylamino)-4(S)-hydroxy-2(R)
-(4-(3-(2-methoxyethoxy)methoxy)propyl)phenylmethyl-6-phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-( 3,6,9-trioxadecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(3,6,9,12-tetraoxatridecyloxy)phenyl] Methyl-hexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3,6,9,12-tetraoxatridecyloxycarbonylamino)-4(S) -Hydroxy-6-phenyl-2(R)-[4-(3,6,9
, 12-tetraoxatridecyloxy)phenyl]methylhexanamide or N-(2(R)-hydroxy-
1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2-phosphoryloxyethoxy)
phenyl)methyl-6-cyclohexylhexanamide, or a pharmaceutically usable salt thereof.

Preferred compounds in this list are A:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-
(2-(hydroxy)ethoxy)phenyl)methyl-6
-cyclohexylhexanamide, B:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-
(1,4,7-trioxaoctyl)phenyl)methyl-6-phenylhexanamide, C:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-
(2-(hydroxy)ethoxy)phenyl)methyl-6
- phenylhexanamide,

D:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-2(R)-((
4-(2-hydroxy)ethoxy)phenyl)methyl-
6-phenylhexanamide, E:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(2-(2-methoxyethoxy)ethoxycarbonylamino)-4(S)-hydroxy-2(R)
-(4-(3-(2-methoxyethoxy)methoxy)propyl)phenylmethyl-6-phenylhexanamide, F:

embedded image N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2
-phosphoryloxyethoxy)phenyl)methyl-6-
Cyclohexylhexanamide, or a pharmaceutically usable salt or ester thereof.

In the compound of the present invention, components A, G, B, J, etc. may have an asymmetric center, and exist as racemic compounds, racemic mixtures, and individual diastereomers, and all isomers are included in the present invention. included in

In any structure or formula I, any variable (eg aryl, heterocycle R, R9, R9a, R9b,
R10, R11, R12, R15, R16, R17, n
, z, etc.) occurs more than once, the definition of each occurrence is independent each time it occurs. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0017] Unless otherwise stated, the term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Me is methyl, Et is ethyl,
Pr is propyl and Bu is butyl). "Alkoxy" refers to an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge. “Alkenyl” means carbonized carbon having one or more unsaturated carbon-carbon bonds present at any stable point in the chain, such as ethenyl, propenyl, butenyl, pentenyl, etc., in a straight or branched configuration. Means to include hydrogen chains. "Halo" as used herein means fluoro, chloro, bromo and iodo. “Counterion” refers to small monovalent negatively charged ions such as chlorine, bromine, hydroxyl, acetic acid, trifluoroacetic acid, perchloric acid, nitric acid, benzoic acid, maleic acid, tartaric acid, hemi-tartaric acid, benzenesulfonic acid, etc. used for.

[0018] Unless otherwise stated, "aryl" as used herein shall mean phenyl (Ph) or naphthyl. "Carbocycle" shall mean any stable 5- to 7-membered carbocycle or 7- to 10-membered bicyclic carbocycle, either of which may be saturated or partially saturated.

Unless otherwise specified, heterocycle as used herein refers to a saturated or unsaturated stable 5-7
Represents a membered monocyclic, bicyclic, or stable 7- to 10-membered bicyclic heterocycle, consisting of a carbon atom and 1 to 3 heteroatoms selected from the group consisting of N, O, and S, nitrogen and The sulfur heteroatom may be optionally oxidized, the nitrogen heteroatom may be optionally quaternized, and any heterocycle defined above includes a bicyclic group fused to a benzene ring. The heterocycle may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Specific examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, Pyrazolyl, pyrazolidinyl, imidazolyl, imidazolyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinol Nil , benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,
Includes thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl. Morpholino is the same group as morpholinyl.

Pharmaceutically usable salts (as water- or oil-soluble or dispersible products) of the compounds of formula I include the conventional non-toxic salts or quaternary ammonium salts of these compounds;
For example, they are generated from inorganic or organic acids or bases. Specific examples of such acid addition salts include acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfone acid salt, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
oxalate, pamate, pectate, persulfate, 3-
phenylpropionate, picrate, pivalate,
Includes propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Examples of base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, dicyclohexylamine salts, and organic bases such as N-methyl-D-glucamine. It includes salts and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may also include lower alkyl halides such as methyl chloride, bromide and iodide, ethyl, propyl and butyl; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate; long chain halides such as chloride, bromide and Can be quaternized with agents such as decyl, lauryl, myristyl and stearyl iodides; aralkyl halides such as benzyl bromide and phenethyl.

The HIV protease inhibitor of formula I is
-III. In general, once the G component is produced, the remaining synthesis follows the principle of amide bond production by coupling methods in liquid phase or solid phase peptide synthesis. Addition and removal of one or more protecting groups are also typical practices.

The amide coupling used to produce the compounds of the invention is typically carried out by the carbodiimide method with dicyclohexylcarbodiimide or 1-ethyl-carbodiimide.
This is done with reagents such as 3-(3-dimethylaminopropyl)carbodiimide. Other methods of generating amide or peptide bonds include, but are not limited to, acid chloride, azide, mixed anhydride, or active ester synthetic routes. Typically, liquid phase amide coupling is performed, but solid phase synthesis by conventional Merrifield techniques can be used instead.

Several schemes for preparing compounds of formula I are shown below. The examples illustrate in detail the application of the following schemes to individual compounds. Other schemes and additional information on the background of the synthesis can be found in European Patent No. 0337714
No.; U.S. Pat. No. 4,661,473, Evans, B.;
E. et al., J. Org. Chem. Volume 50, No. 4
615 pages, 1985 (Evans. B. E.
t. al. J. Org. Chem. 50,461
5 (1985)); Luly, J. R.
et al., J. Org. Chem. Volume 52, No. 1
487 (1987) and cited for these purposes.

One scheme for producing key intermediates related to this invention is shown below.

[Chemical formula 19]

Nucleophilic addition of ethyl propionate to aldehyde 1 in the presence of a deprotonating agent (eg LDA) to form 2
get. Hydrogenation in the presence of a palladium, platinum or rhodium catalyst followed by acid catalysis gives the lactone 3. The second R9 is then prepared by nucleophilic addition reaction of lactone 3 with the halogenated R9 in the presence of a deprotonating reagent.
Add a group. The resulting R9-substituted lactone 4 can be obtained from the above-cited B. E. Evans et al. J. Org. Chem
．． It can also be synthesized from an epoxide intermediate according to Vol. 50, p. 4615 (1985).

The lactone is cleaved by base hydrolysis of 4. The γ-oxyacid is then silylated to prevent relactonization to yield 5. Further coupling by conventional known techniques followed by removal of the silyl group (e.g. Bu4N
+F-) to obtain a compound of formula I.

[0027] Also, some of the important intermediates in the synthesis of the compounds disclosed in the present invention are produced by the following reactions.

embedded image In the formula, R21Br is Br[((C
H2)mO)n]R13 and is a typical alkylating agent that produces compounds having the substituent R9 of the present invention in this scheme.

Certain carbamates in the present invention are prepared according to Scheme III.

[C21]

Reagents A and B for producing carbamates are prepared by reacting the appropriate alcohol with p-nitrophenylchloroformate or with phosgene (or triphosgene) and N-hydroxysuccinimide according to the following formula.

embedded image In the formula, R20 includes alcohols included in the definition of A,
It can also be derivatized with suitable protecting groups such as trialkylsilyl or benzyl.

The compounds of this invention are useful in inhibiting HIV protease, preventing or treating human immunodeficiency virus (HIV) infection, and treating consequent pathological conditions such as AIDS. The treatment of AIDS or the prevention or treatment of HIV infection covers a wide range of symptoms of HIV infection, namely AIDS, ARC
(AIDS-related syndrome), defined as including, but not limited to, both symptomatic and asymptomatic actual or potential infection with HIV. Specifically, the compounds of the present invention are useful in treating HIV infection after exposure to HIV is felt, for example, by blood transfusion, accidental needle stick, or contact with patient's blood during surgery.

In the present invention, compounds having asymmetric centers can exist as racemates, racemic mixtures and individual diastereomers, and all isomeric forms of the compounds are included in the present invention.

For these purposes, the compounds of the present invention can be administered orally, parenterally (subcutaneously, intravenously, intramuscularly, intramuscularly, or (including intrasternal injection or infusion), inhalation spray, or rectal administration.

Accordingly, the present invention further provides therapeutic methods and pharmaceutical compositions for treating HIV infection and AIDS. This method of treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the invention or a pharmaceutically usable salt thereof.

These pharmaceutical compositions can be in the form of orally administrable suspensions or tablets, nasal sprays, sterile injectable preparations, such as sterile injectable aqueous or oily suspensions or suppositories.

When administered orally as suspensions, these compositions are prepared according to techniques well known in the pharmaceutical formulation art and include microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspending agent, Methylcellulose as thickener and sweeteners known in the art/
Flavoring agents may be included. As direct release tablets these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, fillers, disintegrants, diluents known in the art. and lubricants.

When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well known in the pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability. , fluorine carbide, and/or other solubilizing or dispersing agents known in the art.

Injectable solutions or suspensions may be prepared in a suitable non-toxic parenterally acceptable diluent or solvent such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution or a suitable dispersion. The composition may be formulated according to known techniques using sterile, bland fixed oils containing wetting agents and suspending agents such as synthetic mono- or diglycerides and oleic acid.

When administered rectally as suppositories, these compositions incorporate the drug into suitable nonirritating excipients, such as cocoa butter,
It can be prepared by mixing with synthetic glyceride esters or polyethylene glycols, which are solid at room temperature but liquefy and/or dissolve in the rectum to release the drug.

Dosage levels of about 0.02 to 5.0 or 10.0 g/day are useful in treating or preventing the symptoms listed above, with oral doses being 2 to 5 times higher. Specifically, H.I.V.
For infection, administer 10-50 mg of the compound per kg of body weight once a day.
Effectively treated with ~3 doses. However, the specific dosage levels and frequency of dosing for any individual patient may vary and vary depending on the activity of the particular compound used, the metabolic stability and length of action of the compound, the age, weight, and weight of the patient. It will be appreciated that this will depend on a variety of factors including general health, sex, diet, mode of administration and rate of excretion, drug combinations, severity of the individual symptoms and the host being treated.

The present invention also relates to combinations of HIV protease inhibitor compounds and one or more agents useful in the treatment of AIDS.

In particular, the compounds of the invention can be administered in combination with antivirals, immunomodulators, antibiotics or vaccines or other derivatives thereof listed in the following table [Source: Market Letter (Marketlet)
er), November 30, 1987, pp. 26-27,
Genetic Engineering News (Genet
ic Engineering News, January 1988, Volume 8, Page 23].

[0042]
Table 1
A. Antiviral drug drug name
Manufacturer
Indication AL-721
Ethigen
ARC, PGL BETASER
ON Triton Biosciences
AIDS, ARC, KS (interferon β)
(Triton Biosciences) C
ARRISYN Carrington Labs
ARC (Polymannoacetate) (Carrington Labs) CYT
OVENE Syntex
CMV (Ganciclo Will) (Syntex) DDC
hoffman la roche
AIDS, ARC (dideoxycytidine) (Hoffmann-La Roche
) ddI Bristol-Myers AIDS, AR
C (dideoxyinosine) (Bristol
-Myers)──────────────────
────────────────── 1 Abbreviation: AID
S (acquired immunodeficiency syndrome), ARC (AIDS-related syndrome), CMV (cytomegalovirus, which causes opportunistic infections and can lead to blindness or death in AIDS patients), HIV (human immunodeficiency virus, formerly LAV, HTLV-III)
(also known as ARV), KS (Kaposi's sarcoma), PCP (alveolar cysticercosis carinii pneumonia, opportunistic infection), PG
L (persistent systemic lymphadenopathy).

[0043] Drug name
Manufacturer
IndicationFOSCARNET Astra AB HIV infection, (trisodium phosphonoformate) (Astra AB)
CMV, retinitis H
PA-23 Loan・
Paulenxante HIV infection
(Rhon
e-Poulenc Sante) ORNIDYL
mereldau
PCP (eflornithine)
(Merrell Dow) PEPTI
DET Peninsula Loves
AIDS (octapeptide sequence)
(Peninsula Labs) RE
TICULOSE Advanced Virus AIDS, ARC (Nuclear Phosphoprotein) Research (Advance
d Viral
Research) RETRO
VIR Burraffs Welcome AIDS improvement drug
(Burroughs W
ellcome) (zidovudine, AZT)

ARC

pediatric aids

KS, asymptomatic HIV;

non-severe HIV,


Concomitant neurological disease Drug name
Manufacturer
IndicationRIFABUTIN
Adria Loves
ARC (Ansamycin LM427) (Adr
ia Labs) (trimetrexate) Warner-Lambert PCP
(W
arner-Lambert) UA001
Ueno Fine Chemi
AIDS, ARC
Industry (
Ueno Fine
Chem Industry
) VIRAZOLE Viratec/ICN AIDS, ARC
, KS (ribavirin) (Viratek/
ICN) WELLFERON Barafs Urukum KS, HIV,
(alpha interferon) (Burroughs)
Wellcome) ZOVIRAX in combination with AZT AIDS, ARC,
(Acyclovir) (Burroug)
hs Wellcome) AZT
used in conjunction with

B
．． Immunomodulator drug name
Manufacturer
IndicationABPP
upjohn
Progressive AIDS KS
(Upjohn) (Bropyrimine) AMPLIGEN DuPont
) ARC, PG
L (mismatch RNA) HEM Research
(HEM
Research) (Anti-human inter-advanced biotherapy AIDS, A
RC, KS feron antibody) Concepts (Advanced Biotherapy
Conerp
ts) Colony Stimulating Factor Santos Genetics AIDS, A
RC, (GM-CSF) Institute (Sandoz HIV, KS
Gen
etics Institute) CL246, 73
8 American cyanamide
AIDS (CL246, 738)
(American Cynamid) IM
REG-1 Imreg
AIDS, A.R.
C,
(Imreg)
PGL, KSIMREG-2
Imreg
AIDS, ARC,
(Imreg)

PGL, KSIMUTHIOL Merioics Institute AIDS, ARC
(Diethyldithio (Merieux In
(statute) carbamate) drug name
Manufacturer
Indication IL-2
Setas
AIDS, KS (Interleukin-2) (
Cetus)IL-2
HOFFMAN LA ROCHE AID
S, KS (Interleukin-2) Immunex (H
offmann-La Roche
Immunex
) INTRON-A Schering-Plough KS (Interferon α) (Schering-Plough)
ISOPRINOSINE Newport Pharmace ARC, PGL, HIV (Inosine Planobex) Chicalus (Newport
Seropositive patients
Pharmaceu
ticals) (methionine
TNI Pharmaceuticals AIDS,
ARC enkephalin) (TN
I Pharmaceuticals) MTP-PE
ciba geigy
KS (muramyl-tripeptide) (Ciba-Geigy) THYMOPENTI
N(TP-5) Orthopharmaceuticals HIV infection (thymus compound)
(Ortho Pharmaceuti
cals) ROFERON Hoffmann-La Roche KS (Interferon α) (Hoffmann-La Roche
che) (Recombinant Erythro Orthopharmaceuticals AIDS & AZT Treatment Poietin) (Orth
o Pharmaceuticals) Severe anemia associated with TREXAN
DuPont
AIDS, ARC (naltrexone) TNF (tumor necrosis factor) Genentech
ARC, INTERF
(
Genentech)
Combined use with Elon γ

C.
．． Antibiotic drug name
Manufacturer
Indication PENTAM 300
Reformed
PCP (pentamidine)
(LyphoMed) Isethionate)

D. Vaccines Any of the various AIDS or HIV vaccines currently under research and development can be used in combination with the compounds of the present invention or their salts or derivatives to treat or prevent diseases of similar nature caused by AIDS and HIV. . The range of combinations of the compounds of the present invention with AIDS antivirals, immunomodulators, antibiotics, or vaccines is not limited to the above table, but in principle may include combinations with pharmaceutical compositions useful for the treatment of AIDS. It will be understood.

[Example 1] N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2 Preparation of (R)-((4-(2-hydroxy)ethoxyphenyl)methyl-6-phenylhexanamide

Step A: 4-Allyloxybenzyl bromide This compound is synthesized from the known 4-allyloxybenzyl alcohol using triphenylphosphine and tetrabromomethane in methylene chloride. The title compound is 78-
It was purified by distillation at a boiling point of 82°C. NMR (CDCl3): δ 4.49 (s, 2H)
; 4.52(t, 1H); 4.54(t, 1H
); 5.29 (m, 1H); 5.40 (m, 1
H); 6.04 (m, 1H); 6.88 (m,
2H); 7.30 (m, 2H).

Step B: 5(S)-[1'(S)-(
1,1-dimethylethoxycarbonylamino)-2-phenylethyl]-3(R)-4-allyloxyphenylmethyl dihydrofuran-2-(3H)-one lithium diisopropylamide solution is prepared by dihydrofuran (
Dissolve diisopropylamine (1.85 ml) in 20 ml), cool the solution to -10°C, and add 6.6 ml
was prepared by gradually adding a hexane solution of n-butyllithium. Lithium diisopropylamide solution is 5(S)-[1'(S)-(1,1
-dimethylethoxycarbonylamino)-2-phenylethyl]-dihydrofuran-2-(3H)-one (2 g
) was added dropwise to a cold solution (-78°C) of Once the addition was complete, the reaction mixture was allowed to warm to -56°C for over 1 hour and then cooled back to -78°C. A solution of 4-allyloxybenzyl bromide (1.47g) in tetrahydrofuran (20ml) was added dropwise to the reaction mixture at such a rate that the temperature of the reaction mixture did not exceed -75°C. After stirring for 1.5 hours at −78° C., the reaction mixture was warmed to −57° C. for 1 hour and then quenched by the addition of acetic acid in tetrahydrofuran. The solids from the reaction mixture were filtered off and the filtrate was concentrated under vacuum. The residue was partitioned between ether and 10% citric acid. The organic phase was separated, washed with brine and dried (MgS
O4), filtered and concentrated under vacuum to give a solid with an oily residue. Chromatography of this material gave 350 mg of the title compound as an oil.

Step C: 5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyloxy-6-phenyl-2(R)-4-
Allyloxyphenylmethylhexanoate 5(S)-[1'(S)-(1,1-dimethylethoxycarbonylamino)-2-phenylethyl]-3(R)
-4-allyloxyphenylmethyldihydrofuran-2
-(3H)-one (349 mg) was added to dimethoxyethane (
5 ml) and 1N lithium hydroxide (1.5 ml).
ml) was added. After 30 minutes, add 10% citric acid solution (
1.5 ml) was added and the reaction mixture was concentrated under vacuum. The solid residue was partitioned between water and ethyl acetate. The organic phase was separated, washed with brine and dried (Mg
SO4), filtered and concentrated under vacuum to give a white solid. This solid was dissolved in anhydrous dimethylformamide (2
ml) together with imidazole (525 mg) and tert-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature for 16 hours under an argon atmosphere. Water (65 μl) was added to the reaction mixture for 2 hours.
After stirring for an hour, it was concentrated under vacuum. The residue was partitioned between ethyl acetate and 10% citric acid solution. The organic phase was separated, washed with brine, dried (MgSO4) and
Filter and concentrate under vacuum to give an oily residue. Chromatography of this oily residue gave 302 mg of the title compound as a glassy solid.

Step D: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyl Oxy-6-phenyl-2(R)-4
-Allyloxyphenylmethyl-hexanamide 5 (S
)-(1,1-dimethylethoxycarbonylamino)-
4(S)-t-butyldimethylsilyloxy-6-phenyl-2(R)-4-allyloxyphenylmethylhexanoic acid (578 mg), 1-hydroxybenzotriazole (147 mg) and N-ethyl-N' -(3-dimethylaminopropyl)carbodiimide hydrochloride (214 mg) was simultaneously dissolved in 3 ml of anhydrous dimethylformamide under an argon atmosphere. After stirring for 5 minutes,
1(S)-amino-2(R)-hydroxyindan (2
00 mg) followed by triethylamine (3
10 μl) was added. The reaction mixture was stirred at room temperature for 16 hours, concentrated under vacuum and the residue was dissolved in ethyl acetate for 10 hours.
% citric acid solution. Separate the organic phase;
Washed with brine, dried (MgSO4), filtered and concentrated under vacuum to 679ml as a foamy white solid.
The title compound of g was obtained.

Step E: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyl Oxy-6-phenyl-2(R)-[
4-(2-hydroxy-ethoxy)phenyl]methyl-
Hexanamide N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyloxy-
6-phenyl-2(R)-4-allyloxyphenylmethylhexanamide (256 mg) was dissolved in methylene chloride (
5 ml) and methanol (5 ml), and the solution was cooled to -78°C. Ozone was bubbled into the solution until a faint, stable blue solution was obtained. Excess ozone in the reaction vessel was released by bubbling argon through the solution. Next, sodium borohydride (40 mg
) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated under vacuum and the solid residue was partitioned between ethyl acetate and water. Separate the organic phase and dry (
MgSO4), filtered and concentrated under vacuum.

Step F: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl -2(R)-[4-(2-Hydroxyethoxy)phenyl]-methylhexanamide The solid product of Step E was dissolved in a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran and for 2 days at room temperature. Stirred. The reaction mixture was then poured into water and the resulting solid was filtered. This solid was chromatographed to give 165 mg of the title compound as a white crystalline solid, mp 199.4-199.6°C. Analysis calculation value of C35H44N2O7: C, 69.51; H, 7.33;
N, 4.63. Actual value: C, 69.88; H, 7.3
4; N, 4.47.

[Example 2] N-(cis-2(R)-hydroxy-1(S)-indanyl)-5(S)-1,1-
dimethyl-ethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethyl)phenylmethylhexanamide Step A:
3(R)-(4-(2-hydroxyethyl)-phenylmethyl-5(S)-(1(S)-((1,1-dimethylethoxycarbonyl)amino)-2-phenylethyl)dihydrofuran- Preparation of 2-(3H)-one In a 100 ml round bottom flask equipped with a stir bar and argon inlet, (
5(S),1'-(S))-3-carboethoxy-5-
(1-(1,1-dimethylethoxycarbonyl)amino)-2-phenylethyl)dihydrofuran-2-(3H
)-one (1.427 g, 3.78 mmol), absolute ethanol (10 ml), and sodium ethoxide (
0.257g, 3.78mmol) was added. The mixture was stirred for 15 minutes, then 4-(2-hydroxyethyl)-benzyl bromide (0.813 g, 3.78 m
mol) was added little by little. The mixture was stirred at room temperature for 6 hours, then water (10 ml) and lithium hydroxide (0
．． 453g, 18.90ml) was added. The resulting solution was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the residue was suspended in 10% aqueous citric acid. This mixture was extracted portionwise with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine. The solution was dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in 200 ml of toluene and the resulting solution was heated at reflux for 24 hours. The cooled solution was concentrated under vacuum and the residue was chromatographed on 100 g of silica gel using ethyl acetate-hexane 2:3 as eluent. The faster eluting isomer (0.486 g) is the preferred 3 of the title compound.
(R) configuration.

Step B: N-(1,1-dimethylethoxycarbonyl)-5(S)-amino-4(S)-(1
',1'-dimethylethyl-1,1-dimethylsilyloxy-6-phenyl-2(R)-(4-(1',1'-
Preparation of dimethylethyl-1,1-dimethylsilyloxyethyl)phenylmethyl)hexanoic acid In a 100 ml round bottom flask equipped with a stir bar and argon inlet, add the lactone product from Step A (0.486 g, 1.11 mmol).
, dimethoxyethane (6.5ml), water (6.5ml)
), and lithium hydroxide (0.132g, 5.53mm
ol) was added. The mixture was stirred at room temperature for 3 hours, poured into 10% aqueous citric acid, and extracted with ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in dry DMF (13 ml) and imidazole (1.50
5 g, 22.11 mmol) and tert-butyldimethylsilyl chloride (1.666 g, 11.06 mmol)
ol) was added. This mixture was stirred at room temperature for 20 hours. To this solution, methanol (30 ml) was added and the resulting mixture was stirred again at room temperature for 3 hours. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate. This solution was washed with 10% aqueous citric acid, water and brine. Dry (MgSO4), filter, and remove the solvent under vacuum to yield the crude bissilyloxyhexanoic acid. This material was chromatographed on silica gel using 3:97 methanol-chloroform as eluent. 0.249 g of the title compound was obtained as a colorless glass.

Step C: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino)-4(S)-dimethylethyl-1 ,1-dimethylsilyloxy)-6-phenyl-2(R)-(4-(1',1'-dimethylethyl-1,1-dimethylsilyloxyethyl)phenylmethyl)hexanamide Stir bar and argon In a 50 ml round bottom flask equipped with an injection port, add the bis-silyloxy acid product from Step B (0.2
48 g, 0.361 mmol), 2(R)-hydroxy-1(S) aminoindan (0.065 g, 0.43
4 mmol), ethyldimethylaminopropylcarbodiimide hydrochloride (0.083 g, 0.43
4 mmol), hydroxybenzotriazole hydrate (0.059 g, 0.434 mmol), DMF
(3.00 ml), and triethylamine (0.139
ml, 1.00 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a 10% aqueous citric acid solution, and the solution was extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine. Dry (MgSO4), filter, and remove the solvent under vacuum to obtain the crude coupled product. This material was chromatographed on silica gel using 8:92 ethyl acetate-chloroform as eluent. 0.152 g of the title compound was obtained as a colorless glass.

Step D: N-(cis-2(S)-hydroxy-1(R)-indanyl)-5(S)-1,1-
dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethyl)phenylmethylhexanamide in a 25 ml round bottom flask equipped with a stir bar and an argon inlet. Bissilyloxy ether from C (0.152 g, 0.1
86 mmol), and a solution of tetrabutylammonium fluoride in THF (4.0 ml of a 0.5 M solution)
was added. The solution was stirred at room temperature for 19 hours. The reaction mixture was poured into ethyl acetate (150 ml) and the solution was diluted with 10
% citric acid aqueous solution, NaHCO3 saturated aqueous solution, and brine. Dry (MgSO4), filter,
The solvent was then removed under vacuum to obtain the crude product as a white solid. This substance was dissolved in boiling ethyl acetate (10 ml).
) was recrystallized from 0.075 g of the title compound was obtained as finely divided white crystals with a melting point of 221-222°C.

[Example 3] N-(cis-2(S)-hydroxy-1(R)-indanyl)-5(S)-(1,1
-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(3-hydroxypropyl)phenylmethylhexanamide 4-(2-hydroxyethyl)benzyl bromide in step A The title compound was prepared in a manner similar to that described in Example 2 using 4-(3-hydroxypropyl)benzyl bromide in place of . This compound has a melting point of 1
The temperature was 90-192°C.

[Example 4] N-(cis-2(R)-hydroxy-1(S)-indanyl)-5(S)-1,1-
dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-(4-(2-(2-
N-(cis-2(R)-hydroxy-1(S)-indanyl)-5(S)- (1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(2-hydroxyethyl)phenylmethylhexanamide (0.080g, 0.136mm
ol), methylene chloride (5.0 ml), diisopropylethylamine (0.044 ml, 0.250 mmol)
), and 2-methoxyethoxymethyl chloride (0
．． 020ml, 0.160mmol) was added. This solution was stirred at room temperature for 72 hours. The reactant was converted into NaHCO
3 saturated aqueous solution and the methylene chloride was removed under vacuum. The residue was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with brine and dried (MgSO4). The residue obtained after filtration and removal of the solvent under vacuum was chromatographed on silica gel using 2:98 methanol-chloroform as eluent. The chromatographed product was further purified by recrystallization from boiling ethyl acetate. 0.040 g of the title compound was obtained as white crystals with a melting point of 172-173°C.

[Example 5] N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6 -Phenyl-2(R)-(4-(3-(2-methoxyethoxy)methoxypropyl)-phenyl)methylhexanamide Using the method of Example 4, N-(2(R)-hydroxy-1( S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-(4-(3-hydroxypropyl)phenyl)methyl The title compound (melting point 176-177°C) was prepared from hexaneamide.

[Example 6] N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6 -phenyl-2(R)-[4-(1,4,6,9
,12,15,18-heptaoxa-5-oxononadecyl)phenyl]-methylhexanamide N-[2(R
)-hydroxy-1(S)-indanyl]-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-[4-(
2-Hydroxyethoxy)phenyl]methylhexanamide (75 mg) was added to dimethylformamide (5 ml).
60 mg of 3,6,9,12-tetraoxatridecyl-4-nitrophenyl carbonate and 15.4 m
of 4-dimethylaminopyridine at 60° C. for 64 hours. The solvent was removed under vacuum and the oily residue was partitioned between ethyl acetate and 10% aqueous citric acid. The organic phase was separated, washed with 5% ammonia hydroxide solution, then brine, dried (MgSO4), filtered, and concentrated under vacuum to give a semi-solid residue. This residue was chromatographed to give a melting point of 155.0.
Obtained 39 mg of the title compound as a white solid at ~155.5<0>C.

[Example 7] N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6 -phenyl-2(R)-[4-(6-aza-1,
4,9,12,15,18-hexaoxa-5-oxononadecyl)phenyl]-methylhexanamide N-[
2(R)-hydroxy-1(S)-indanyl]-5(
S)-(1,1-dimethylethoxycarbonylamino)
-4(S)-hydroxy-6-phenyl-2(R)-[
4-(2-hydroxyethoxy)phenyl]methylhexanamide (76 mg) was dissolved in tetrahydrofuran (1 ml).
) in 4-nitrophenylchloroformate (50 mg
) and pyridine (20 μl). After 2.5 hours, 50 mg of 2,5,8,11-tetraoxatridecan-13-amine was added to the reaction mixture. After 64 hours the reaction mixture was concentrated in vacuo and the oily residue was chromatographed to 39 m
The title compound was obtained as a solid weighing g.

[Example 8] N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6 -Phenyl-2(R)-[4-(1,4,7-trioxaoctyl)phenyl]methylhexanamide

Step A: 4-(1,4,7-
Preparation of trioxaoctyl)benzyl bromide The conversion of 4-hydroxybenzyl alcohol to the title compound is carried out using 1-bromo-
3,6-dioxaheptane (sodium hydride/DMF
) and then reaction with carbon tetrabromide and triphenylphosphine.

Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl -2(R)-[4-(1,4,7-trioxaoctyl)phenyl]methylhexanamide Following the procedure of Example 1, Steps BD and F, the product of Step A and 5(S)- [1'(S)-(1,1-dimethylethoxycarbonylamino)-2-phenylethyl]dihydrofuran-2-(3H)-one was converted to the title compound. Analysis calculation value of C38H50N2O8: C, 68.86; H, 7.60;
N, 4.23. Actual value: C, 68.99; H, 7.5
4; N, 4.58.

[Example 9] N-[2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6 -phenyl-2(R)-[4-(1,4,7,1
0,13-pentaoxatetradecyl)phenyl]methylhexanamide The known compound N-(2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-(4-hydroxyphenyl)methylhexanamide (45 mg,
Cesium carbonate (0.0599 mmol) was added to a solution of cesium carbonate (5
8.5 mg, 0.179 mmol) and 1-iodo-
3,6,9,12-tetraoxatridecane (190 m
g, 0.599 mmol) was added. This solution was heated at 80℃
The mixture was heated for 12 hours, cooled to room temperature, diluted with chloroform, and filtered through Celite. Upon concentration of this solution, a white solid was recrystallized from ethyl acetate and hexane, melting point 16.
20 mg (44% yield) of alkylated product was obtained at 3-164°C. 1H NMR (300 MHz) δ 7.32-7.
21 (m, 8H), 7.06 (m, 3H), 6
．． 82 (m, 2H), 6.00 (br d, J=
7.6Hz, 1H), 5.23(dd, J=8.
4, 4.8Hz, 1H), 4.91(br d, J
=6.8Hz, 1H), 4.24(m, 1H)
, 4.08 (m, 2H) , 3.93 (br s,
1H), 3.82 (m, 4H), 3.72-3.59
(m, 8H), 3.54-3.51 (m, 2H),
3.35 (s, 3H), 3.00-2.69 (m,
8H), 1.84-1.80 (m, 2H), 1.4
5(d, J=3.6Hz, 1H), 1.38(br
s, 9H). Analysis calculation value of C42H58N2O10: C, 67.18; H, 7.79;
N, 3.73. Actual value: C, 67.02; H, 7.7
5; N, 3.68.

Examples 10-11 Using the method of Examples 8 or 9 and substituting the appropriate alkylating agent, the following materials were prepared. N-[2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R
)-[4-(1,4,7,10-tetraoxaundecyl)phenyl]methylhexanamide C40H54
Analytical calculated value of N2O9: C, 67.97; H, 7.70;
N, 3.96. Actual value: C, 67.40; H, 7.5
1; N, 3.57. N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R
)-[4-(1,4-dioxapentyl)phenyl]methylhexanamide C36H46N2O7 Analysis calculation: C, 69.88; H, 7.49;
N, 4.53 Actual value: C, 69.59
; H, 7.45; N, 4.46.

[Example 12] Dilithium N-(2(
R)-hydroxy-1(S)-indanyl)-5(S)
-(1,1-dimethylethoxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-((4
-(2-phosphoryloxy)ethoxy)-phenyl)methyl)hexanoic acid amide
Step A: N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-
Preparation of phenyl-2(R)-[(4-(2-dibenzylphosphoryloxyethoxy)phenyl)methyl]hexanoic acid amide Phosphorizing agent [bis(benzyloxy) used in the following procedure]
-(N,N-diisopropylamino)phosphine] by W. Bannwarth and A. Trzeciak, Helv. Kim. Actor. (Helv. Chim.
Acta. ), (1987), Vol. 70, p. 175. N-(2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-((4-
(2-Hydroxy)ethoxy)phenyl)methyl)hexanoic acid amide (103 mg, 0.17 mmol) and tetrazole (28 mg, 0.40 mmol) at 70%
μl (0.21 mmol) of [bis(benzyloxy)
-(N,N-diisopropylamino)phosphine] was added. After 40 minutes an additional 40 μl of phosphine and 15
mg of tetrazole was added and stirring continued for 20 minutes. m-chloroperoxybenzoic acid (138 mg, 0.4 mmol of 50-60% purity) was added and the mixture was stirred for 1 hour. The mixture was diluted with EtOAc and washed sequentially using 5% NaHSO3, 10% NaHCO3 and brine. After drying, the solvent was evaporated and the residue was dissolved in silica gel (1-5% MeOH
/CHCl3). 70 mg of the title compound were obtained after crystallization from ethyl acetate/hexane.

Step B: Dilithium N-(2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-[(4-
(2-Phosphoryloxyethyl)phenyl)methyl]hexanoic acid amide The product of Step A was dissolved in 15 ml of 95% ethanol and 35 mg of 10% Pd/C was added. This mixture was stirred for 1.5 hours under a hydrogen atmosphere. Lithium hydroxide (
1N solution, 165 μl) was added and the mixture was diluted with water and filtered through Celite. The Celite pad was washed with ethanol and water. Most of the solvent was removed on a rotary evaporator and the residue was filtered through a 0.45 μm membrane and lyophilized to give 60 mg of the title compound as a fluffy white powder with a melting point >300°C.

[Example 13] Dilithium N-(2(
R)-hydroxy-1(S)-indanyl)-5(S)
-(1,1-dimethylethoxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-[(4
-(3-Phosphoryloxypropyl)-phenyl)methyl]hexanoic acid amide Application of the method of Example 12 to the preparation of Example 3 gave the title compound with a melting point >300<0>C.

[Example 14] [5(S)-(1,1-dimethylethoxycarbonyl-amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-(2-hydroxyethoxy ) phenyl)methylhexanoyl]-valine-N-3,6,9,12-tetraoxatridecylamide
Process A: N-3, 6, 9, 12
- Tetraoxatridecylvalineamide A solution of the N-hydroxysuccinimide ester of BOC-L-valine in dimethyloxyethane is treated with 1 equivalent of the known 13-amino-2,5,8,11-tetraoxatridecane. The title compound was obtained as an oil.

Step B: [5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-
6-phenyl-2(R)-(4-(2-hydroxyethoxy)phenyl)methylhexanoyl]-valine-N-
3,6,9,12-tetraoxatridecylamide 2 (
R)-hydroxy-1(S)-aminoindan in step A
Example 1, Step D
Further rearrangement was carried out using the method of Example 1, Steps E and F to give the title compound as a solid with a melting point of 142-143.5°C. C40H63N3 O11・0.3H2 O
Analysis calculated value: C, 62.61; H, 8.35;
N, 5.48. Actual value: C, 62.58; H, 8.2
2; N, 5.43.

[Example 15] [5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(4-(2-hydroxyethoxyphenyl) ) Methylhexanoyl]-valine-
N-3,6,9,12,15-pentaoxapentadecylamide Using the method of Example 14, but with 13-amino-2,5
, 8,11-Tetraoxatridecane was replaced with 3,6,9,12,15-pentaoxapentadecylamine in Step A to give the title compound as a white solid with a melting point of 133-141°C. . Analysis calculation value of C41H65N3 O12: C, 60.65; H, 8.06;
N, 5.15. Actual value: C, 60.84; H, 8.0
0; N, 5.12.

[Example 16] N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2 (R)-((4-(2-hydroxy)ethoxy)phenyl)methyl-6-cyclohexylhexanamide
Step A: (5S, 1′S)-5-
(1'-(1,1-dimethylethoxycarbonyl)amino)-2'-cyclohexylethyl)-4,5-dihydrofuran-2-(3H)-oneThe known (5S,1'S)-5-( 1'-(1,1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-(3H)-one was dissolved in ethyl acetate and rhodium on alumina was added. . This mixture was placed in a Parr apparatus and under a hydrogen atmosphere (
50 psi) and 50° C. overnight. Filtration and evaporation of the solvent gave the title compound as a viscous oil that gradually solidified to a hard glass.

Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyl Oxy-2(R)-(4-benzyloxyphenyl)methyl-6-cyclohexylhexanamide The product of Step A was prepared by the method of Example 1, Steps B-D.
In step B, benzyloxybenzyl bromide was used in place of allyloxybenzyl bromide to convert to the title compound.

Step C: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyl Oxy-2(R)-(4-hydroxyphenyl)methyl-6-phenylhexanamide Step B
The product was dissolved in ethanol containing 10% Pd/C and stirred under hydrogen atmosphere for 18 hours. The mixture was filtered and the solvent was evaporated to give the title compound.

Step D: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyl Oxy-2(R)-(4-(2-hydroxy)ethoxy)phenyl)methyl-6-cyclohexylhexanamide N-(2(R)-hydroxy-1(S)-indanyl)-5 in 20 ml of dioxane (S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyloxy-2(R)-(4-hydroxyphenyl)methyl-6-cyclohexylhexanamide (800 mg, 1. Cesium carbonate (1.15 g, 3.52 mmol) was added to the solution (17 mmol), and the mixture was heated to 80° C. under argon gas. Ethyl bromoacetate (0.195 ml, 1.76 mmol) was added portionwise and heating continued for 3.5 hours. After cooling the mixture to room temperature, 100 ml of chloroform was added, the mixture was filtered, and the solid was washed three times with 30 ml of chloroform. The filtrate was evaporated to give 918 mg of solid. This was dissolved in 16 ml of DME, and THF (2.3 ml, 4
．． 7 mmol) of 2.0 M lithium borohydride was added dropwise. After stirring for 1.5 hours under argon gas, the reaction was carefully quenched with 20 ml of 1M citric acid solution. The organic solvent was removed under reduced pressure and the aqueous residue was extracted twice with 40 ml of ethyl acetate. The combined organic layers were washed with water, 10% sodium carbonate, brine, and dried over magnesium sulfate. Removal of the solvent under reduced pressure yielded 853 mg (100 mg) as a colorless foam.
%) of the title compound was obtained.

Step E: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R )-(4-(2-(hydroxy)ethoxy)
phenyl)-methyl-6-cyclohexylhexanamide silyl ether derived from Step D (2.55 g, 3
．． 52 mmol) in 20 ml of 1M TBAF/TH
F and stirred under argon gas for 24 hours. An additional 7 ml of TBAF solution was added and stirred overnight. Further T
BAF solution was added and the reaction was stirred for 6 hours, then warmed to 35° C. for 4 hours. After slow cooling, the reaction mixture was poured into a stirred mixture of 45 ml of 1M citric acid and 150 ml of ice water. After stirring for 15 minutes, the precipitate was collected by filtration and washed with water. The solid was dissolved in CHCl3 and Na2SO
4 to remove the solvent and obtain a yellow solid. This was crystallized from 1:1 ethyl acetate-hexane with a melting point of 1
The title compound was obtained as colorless crystals at 67-168°C. Analysis calculation value of C35H50N2O7: C, 68.83; H, 8.25;
N, 4.59. Actual value: C, 68.44; H, 8.3
0; N, 4.61.

[Example 17] N-(4-fluoro-2(
R)-hydroxy-1(S)-indanyl)-5(S)
-(1,1-dimethylethoxycarbonylamino)-4
(S)-hydroxy-2(R)-(4-(2-(hydroxyethoxy)phenyl)methyl-6-phenylhexanamide
Step A: 4-fluoro-2-hydroxy-2
,3-dihydro-(1H)-inden-1-one 10m
1.0 g (6.66 mmol) of 4-fluoro-
The 1-indanone solution was added dropwise. After 1.5 hours of cooling stirring, 3.22 g (9.99 mmol) of iodobenzenediacetate was added in four portions over a period of 1.3 hours. The cooling bath was removed and stirring continued for 2 hours. The solvent was removed under reduced pressure to obtain a residue. Add 100ml of this 1:1
of ethyl acetate-ethyl ester and the solids were removed by filtration. The filtrate was evaporated under reduced pressure to give an oil. This was dissolved in 15 ml of ethanol and treated with 10 ml of 10% HCl for 45 minutes under argon gas. The solvent was removed under reduced pressure to obtain a residue. This was dissolved in 120 ml of 1:1 ethyl acetate-ethyl ester and washed with saturated NaHCO3, brine and the Mg
Drying over SO4, treatment with activated charcoal and removal of solvent under reduced pressure gave an amber oil. This substance at a ratio of 1:3
75g fine SiO2 using EtOAc-hexane
538 mg (4
9%) of the hydroxylated product was obtained.

Step B: cis-1-amino-2-hydroxy-4-fluoro-2,3-dihydro-(1H)-
Indene 6.0g (36.1mmol) in 80ml pyricin
3.0 g (36
．． 1 mmol) of methoxylamine was added and the solution was stirred for 0.5 h under argon gas. The solvent was removed under reduced pressure and the residue was dissolved in 350 ml of EtOAc and washed with 10% HCl, water, saturated NaHCO3, brine, dried over MgSO4 and the solvent was removed to give a dark oil. . Dissolve this material in 50 ml of dry THF.
(96.8 mmol) in THF at 0 °C.
l) was added dropwise to 1.0M borane. After this addition, the cooling bath was removed and stirring continued for 2.5 days. The reaction was then heated at 50 °C for 2 h, cooled to room temperature, and 30 m
The reaction was carefully quenched with 1 liter of methanol. The solvent was removed under reduced pressure and the residue was dissolved twice in 30 ml methanol and evaporated to give a foam. This is 90:
10:1 CHCl3-CH3OH-NH4OH
was chromatographed on 500 mg of finely divided SiO2 using 1.385 g (23%
) was obtained. This product was used by Evans et al.
of Organic Chemistry (J. Org.
Chem. ) (1985) Volume 50, Page 4615]
phenylalanyl amide was resolved into its optical isomers using the method of The less polar diastereomer is the desired 1(S)-amino-4-fluoro-2(R)-
Obtained as hydroxyindan.

Step C: N-(4-fluoro-2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-t-butyldimethylsilyloxy-2(R)-(
4-Benzyloxyphenyl)methyl-6-phenylhexanamide 1(S)-Amino-
4-fluoro-2(R)-hydroxyindan, 5(
S)-(1,1-dimethylethoxycarbonylamino)
-4(S)-t-butyldimethylsilyloxy-2(R
)-(4-benzyloxyphenyl)methyl-6-phenylhexanoic acid (see EPO 337 714).

Step D: N-(4-fluoro-2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-t-butyldimethylsilyloxy-2(R)-(
4-Hydroxyphenyl)methyl-6-phenylhexanamide The product of Step C (130 mg) was added to 30 mg of 10% Pd.
/C in 4 ml of ethanol and stirred under hydrogen atmosphere for 18 hours. The mixture was filtered and the solvent was evaporated to give 88 mg of the title compound.

Step E: N-(4-fluoro-2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-Hydroxy-2(R)-(4-hydroxyethoxyphenyl)methyl-6-phenylhexanamide The product of Step D was converted to the title compound by the method of Example 16 (Steps D and E). This product is a solid;
Chromatographed with 10 mg of fine SiO2,
A residue was obtained. This was triturated with EtOAc-hexane to give 38% as a colorless solid with a melting point of 206-209°C.
mg of the title compound was obtained. C35H43N2 O7 ・0.4H2 O
Analysis calculation value: C, 66.74; H, 7.00;
N, 4.45. Actual value: C, 66.74; H, 6.8
3; N, 4.34.

[Example 18] N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2 (R)-(4-(4-hydroxy-2-thiabut-1-yl)phenyl)methyl-6-phenylhexanamide
Step A: (5S,3R,1'S)-3-(4-bromomethyl)phenyl)methyl-5-(1'-((1,
1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-(3H
)-one in 8 ml dry THF (1.39 ml (9.9 mmol
) of 6.14 ml (9.82 mmol) of diisopropylamine in hexane.
6M n-butyllithium under argon gas at 0°C.
So I added it slowly. After stirring for 10 minutes at 0°C, the flask was cooled to -78°C. 1.5 g (4.91 mmol) of 5(S)-(1') in 8 ml of THF
A solution containing (S)-((1,1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-(3H)-one was added dropwise to 1 ml. Rinse with THF. After the addition, the solution was stirred at -78°C for 20 minutes. Next 2
3.89g (14.7mmol) in 4ml THF
of α,α'-dibromo-p-xylene at -78°C via a jacketed addition funnel. The solution was stirred at -78°C for 1.5 hours and warmed to -50°C for 20 minutes. The reaction was then stopped by rapidly adding 15 ml of 1M citric acid. The mixture was diluted with 15 ml of water and extracted twice with ether. The combined organic layers were washed with water, 10% Na2CO3, brine, dried over Na2SO4 to remove the solvent,
An oil was obtained. This was combined with 40 g of finely divided SiO2 using CHCl3 and then 1:1 ethyl acetate-hexane.
Chromatographed. 100 g of the product containing the fractionated portion was prepared using 1:4 EtOAc-hexane.
Rechromatography on finely divided SiO2 gave 351 mg of bromomethylphenyllactone as a colorless oil.

Step B: (5S,3R,1'S)-3-(
(4-hydroxy-2-thiabut-1-yl)phenyl)methyl-5-(1'-((1,1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,
5-dihydrofuran-2-(3H)-one The product from step A (78 mg, 0.16 m
80 μl (1.14 mol) of
mmol) of mercaptoethanol and 80 μl (0
．． 459 mmol) of diisopropylethylamine was added. After stirring for 0.5 hours, the reaction mixture was poured into 1M citric acid and extracted twice with ethyl acetate. The combined organic layers were washed with water, 10% Na2CO3, brine, and Na
Drying over 2SO4 and removal of solvent gave an oil. Using 99:1 CHCl3-CH3OH,
Chromatography on 5 g of finely divided SiO2 gave 52 mg (67%) of the thioether as a colorless oil.

Step C: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R )-(4-(4-Hydroxy-2-thiabut-1-yl)phenyl)methyl-6-phenylhexanamide The product from Step B was converted to the silyl protected acid to give 2(R
)-hydroxy-1(S)-aminoindan and TBAF/TH by the appropriate method of Example 1.
Treatment with F gave a colorless solid. This was dissolved in 5% using CHCl3-CH3OH from 99:1 to 97:3.
Chromatography on fine SiO2 gave a solid. This was triturated with 1:4 EtOAc-hexane to give 31% as a colorless solid with a melting point of 196-198°C.
mg (46%) of the title compound was obtained. C36H46N2 O6 S・0.1H2 O
Analysis calculated value: C, 67.92; H, 7.31;
N, 4.40. Actual value: C, 67.70; H, 7.5
1; N, 4.24.

Example 19 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxy-carbonylamino)-4(S)-hydroxy-2(R)-(4-(
2-Hydroxyethylsulfonylmethyl)phenyl)methyl-6-phenylhexanamide

Process A: 5
(S)-(1,1-dimethylethoxy-carbonylamino)-4(S)-t-butyldimethylsilyloxy-2
(R)-(4-(2-Hydroxyethylsulfonylmethyl)-phenyl)methyl-6-phenylhexanoic acid Example 18 The intermediate silyl protected acid prepared in step C (50 mg, 0.068 mmol) was added to 2 ml of ethanol.
1 and treated with a solution of 63 mg (0.102 mmol) of potassium peroxymonosulfate in 1 ml of ethanol at room temperature for 3 hours. Solid NaHCO3 was then added and the pH
was made neutral and then saturated NaHCO3 was added. The reaction mixture was extracted in two portions with ethyl acetate, the combined organic phases were washed with water and brine, dried over MgSO4 and the solvent was removed under reduced pressure to give the sulfone as a colorless oil. Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl-amino)-4(S)-hydroxy-2(R)-
(4-(2-hydroxyethyl-sulfonyl-methyl)
Phenyl)methyl-6-phenylhexanamide Step A
The product was combined with 2(R)-hydroxy-1(S)-amino-indan and treated with TBAF/THF by the method described in Example 1 to give a colorless solid. This solid was chromatographed on 7 g of finely divided SiO2 using 95:5 CHCl3-CH3OH to give 14 mg of the title compound as a colorless solid (30%
) was obtained. m. p. 220-223℃ Elemental analysis: C36H46N2 O8 S・0.75 H
Calculated value for 2O: C, 63.56; H, 7
．． 04; N, 4.11 Actual value: C, 63.36
; H, 6.82; N, 3.87

Example 20 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2
,5,8,11,14-pentaoxapentadec-1-
yl)phenyl)methyl-6-phenylhexanamide
Step A: (5(S), 3(R)
,1'(S))-3-(4-(2,5,8,11,14
-pentaoxapentadec-1-yl)phenyl)methyl-5-(1'-((1,1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-( 3H)-one Product from Example 18 Step A (
183 mg, 0.375 mmol) of tetraethylene glycol monomethyl ether (84 liters, 0.432 mmol) and silver(I) oxide (100 m
g, 0.432 mmol) was added. After stirring for 4 days at room temperature, the reaction mixture was evaporated as eluent from 95:5 to 90:10.
fine SiO2 using CHCl3-CH3OH
Filtration was performed through 5 g. Removal of the solvent gave 100 mg (43%) of ether as a colorless oil. Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(
4-(2,5,8,11,14-pentaoxapentadec-1-yl)phenyl)methyl-6-phenylhexanamide The product from Step A is converted to the silyl protected acid, 2(R)
-hydroxy-1(S)-amino-2,3-dihydro-
(1H)-indene and according to Example 1, TB
Treatment with AF/THF gave a colorless solid. This solid is 9
Fine S using 2:8 CHCl3-CH3OH
Chromatography on 5g iO2 gave a solid. This was triturated with 1:4 EtOAc-hexane to give 40 mg (32%) of the title compound as a colorless solid.
I got it. m. p. 145-147°C Elemental analysis: Calculated value for C43H60N2O10: C, 67.52; H, 7.91; N, 3.
66 Actual value: C, 67.46; H, 8.11;
N, 3.64

Example 21 N-(4-(3,4-dihydro-(1H)-benzo[c
[Thio-pyranyl-2,2-dioxidene))-5(S
)-(1,1-dimethylethoxycarbonyl-amino)
-4(S)-hydroxy-6-phenyl-2(R)-(
4-(3-hydroxypropyl)phenylmethylhexanamide
Step A: N-(4-(3,4-dihydro-(1H)-benzo[c]thiopyranyl-2,2-dioxide))-5(S)-(1,1-dimethylethoxycarbonylamino)-4 (S)-((1',1'-dimethylethyl-1,1-dimethylsilyloxy)-6-phenyl-2(R)-(4-(3-[1',1'-dimethylethyl-1 ,1-dimethylsilyloxy]propyl))
-Phenylmethylhexanamide N'-(1,1-dimethylethoxycarbonyl)-5(
S)-amino-4(S)-(1',1'-dimethylethyl-1,1-dimethylsilyloxy)-6-phenyl-
2(R)-(4-[1',1'-dimethylethyl-1,
1-Dimethylsilyloxypropyl]phenyl)methyl)hexanoic acid (805 mg, 1.15 mmol), the intermediate prepared in Example 3, was dissolved in 5 ml of dry DMF and to this solution was added 1-(3-dimethylaminopropyl). )-3-ethylcarbodiimide hydrochloride (255
mg, 1.33 mmol), N-methylmorpholine (3
05 μL, 2.76 mmol), 1-hydroxybenzotriazole hydrate (180 mg, 1.33 mmol) and known compound ±4-amino-3,4-dihydro-(1H)-benzo[c]thiopyran hydrochloride (
290 mg) was added. After stirring for 18 hours under an argon atmosphere, the mixture was concentrated to dryness under vacuum and the residue was purified with EtO
Partitioned between Ac and water and acidified to pH 3 with 10% citric acid. The phases were separated and the aqueous phase was extracted once more with EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. The solvent was removed to obtain 1.1 g of oil, which was added to 55 m
flash chromatography on a m column eluting with 4 liters of 2% EtOAc in chloroform followed by 2 liters each of 3%, 5% and 10% EtOAc in chloroform. The unwanted diastereomer (410 mg) eluted first, followed by 310 mg of the title compound. Successive elutions with 35% EtOAc gave both diastereomers of the compound desilylated at the primary hydroxyl group (undesired isomer 1
20 mg, then 65 mg of the isomer corresponding to the title compound.
). Step B: N-(4-(3,4-dihydro-(1H)-benzo[c]thiopyranyl-2,2-dioxide))-5
(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-
(4-(3-Hydroxypropyl)phenyl)methylhexanamide 310 mg (0.37 mmol) of the title compound from Step A was deprotected by the method of Example 1 Step F. The crude white solid obtained from this step was dissolved in 5 ml of methanol and this solution was added with 5 ml of potassium peroxymonosulfate in 5 ml of water.
A solution containing 20 mg (0.85 mmol) was added. 2
After stirring at 5° C. for 18 hours, the mixture was concentrated under reduced pressure and the residue was extracted with a chloroform/saturated aqueous sodium bicarbonate mixture. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed to give a gel which was subjected to flash chromatography eluting with 2% methanol in methylene chloride followed by a gradient of 4% to 7% in methylene chloride. The title compound was obtained as a white solid which was triturated with ether. m. p. 197-199°C Elemental analysis: Calculated value for C36H46N2O7S: C, 66.44; H, 7.12; N, 4
．． 30 Actual value: C, 66.13; H, 7.11
; N, 4.24

Example 22 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(5-thia-7-hydroxy-2(E)-hepten-1-yl)-
6-phenylhexanamide

Step A: (5S,3R,1'S)-3-(4-bromo-2(
E)-buten-1-yl)-5-(1'-((1,1-
dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-(3H)-
1.6 M n-butyllithium in hexane at a slow flow rate to a stirred solution of 1.93 ml (13.75 mmol) diisopropylamine in 12 ml dry THF under Ar at 0°C.
19 ml (13.09 mmol) was added. 1 at 0℃
After 0 min of stirring, the flask was cooled to -78°C and TH
A solution of 2.0 g (6.55 mmol) of lactone in 12 ml of F was added dropwise. After the dropwise addition, the solution was stirred for 20 min at -78°C and then 1,4-dibromo-2(
E)-butene 4.2 g (19.6 mmol) at -78°C
solution through a coated addition funnel at -78°C. The solution was stirred at -78°C for 0.5 hour, and then 16 ml of 1M citric acid was added rapidly to stop the reaction. The mixture was diluted with 15 ml of water and extracted with ether in three portions. The combined organic phase was mixed with water, 10% Na2CO3,
Washing with brine, drying over Na2SO4 and removal of solvent gave an oil which was chromatographed on 200 g of powdered SiO2 using 1:4 ethyl acetate-hexane. This gave 1.97 g (69%) of the title compound as a colorless oil. Step B: (5S,3R,1'S)-3-(5-thia-7
-Hydroxy-2(E)-hepten-1-yl)-5-
(1'-((1,1-dimethylethoxycarbonyl)-
Amino)-2'-phenyl-ethyl)-4,5-dihydrofuran-2-(3H)-one The product from step A (15
To a stirred solution of 0 mg, 0.342 mmol) was added 150 μl (2.14 mmol) of mercaptoethanol and 150 μl (1.07 mmol) of triethylamine. After stirring for 1 hour, the reaction mixture was poured into water and extracted in two portions with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na2SO4 and the solvent removed to give 146 mg (98%) of the thioether as a colorless oil.
) was obtained. Step C: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(
5-thia-7-hydroxy-2(E)-heptene-1-
yl)-6-phenylhexanamide The product from Step B was converted to the title compound by the method of Example 1, Steps C, D and F, and the resulting colorless solid was dissolved in 3.5 m ethyl acetate.
The title compound 81m was crystallized from l as a colorless solid.
g (41%) was obtained. m. p. 160-161°C Elemental analysis: Calculated value for C32H44N2O6S: C, 65.73; H, 7.58; N, 4
．． 79 Actual value: C, 66.00; H, 7.66
; N, 4.81

Example 23 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(5-thia-8-hydroxy-2(E)-octen-1-yl)-
6-phenylhexanamide

Step A: (5S,3R,1′S)-3-(5-thia-8-hydroxy-2(E)-octen-1-yl)-5-(1
'-((1,1-dimethylethoxycarbonyl)amino)-2'-phenylethyl)-4,5-dihydrofuran-2-(3H)-one Bromo prepared in Example 22 Step A in 2.3 ml DMF To a stirred solution of butenyl lactone (142 mg, 0.324 mmol) was added 3-mercaptopropanol 1
50 μl and 150 μl (1.07 mmol) of triethylamine were added. After stirring overnight, the reaction mixture was heated to 50 °C.
150 μl each of mercaptopropanol and triethylamine were added, and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was poured into water and diluted with ethyl acetate.
Extracted in batches. The combined organic phases were washed with water and brine, dried over Na2SO4 and the solvent was removed to give an oil which was chromatographed on 5 g of fine SiO2 using 2:3 EtOAc-hexane. , thioether 56m as a colorless oil
I got g. Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl-amino)-4(S)-hydroxy-2(R)-
(5-thia-8-hydroxy-2(E)-octene-1
-yl)-6-phenylhexanamide The product from Step A was converted to the title compound by the method of Example 1 Steps C, D and F to give a colorless solid which was purified by 98:2 CH
10g fine SiO2 using Cl3-CH3OH
The resulting residue was chromatographed on 1:
Trituration of 4 with EtOAc-hexane gave 35 mg of the title compound as a colorless solid. m. p. Soften at 141-143℃, 156-158
Melting elemental analysis at °C: Calculated for C33H46N2O6S: C, 66.19; H, 7.74; N, 4
．． 68 Actual value: C, 65.85; H, 7.68
; N, 4.42

Example 24 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(5,8,
11,14,17-pentaoxaoctadec-2(E)
-en-1-yl)-6-phenylhexanamide

Step A: (5S, 3R, 1
'S)-3-(5,8,11,14,17-pentaoxaoctadec-2(E)-en-1-yl-5-(1'
-((1,1-dimethylethoxycarbonyl)-amino)-2'-phenyl-ethyl)-4,5-dihydrofuran-2-(3H)-one in 1.7 ml of ether Example 2
Bromobutenyl lactone produced in Step 2 A (
139 mg (0.6 mmol) of silver(I) oxide and 117 μl (0.6 mmol) of tetraethylene glycol monomethyl ether were added to a stirred solution of 224 mg (0.51 mmol) of silver(I) oxide. After stirring during the weekend, the reaction mixture was eluted with 95:5 CHCl3-CH3OH and filtered through 3.5 g of finely divided SiO2 to give 227 mg of tetraethylene glycol ether as a colorless oil. Step B: N-(2(R)-hydroxy-1(S)-indanyl)5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(5
,8,11,14,17-pentaoxaoctadec-2
(E)-en-1-yl)-6-phenylhexanamide The product from Step A was converted to the title compound by the method described in Example 1 Steps C, D and F to give a colorless solid,
This was converted into 96.5:3.5:0.14 EtOAc-C
Fine SiO2 1 using H3OH-NH4OH
Chromatography on 0g gave 60mg of the title compound as a colorless solid. m. p. 118-120℃ Elemental analysis: C39H58N2 O10・0.5 H2O
Calculated value for: C, 64.71; H, 8.
22; N, 3.87 Actual value: C, 64.79;
H, 8.25; N, 3.86

Example 25 N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2
(R)-[4-(2-hydroxyethoxy)phenyl]
Methylhexanamide step A: 2-[N-(1',2'-di-t-butoxy-
Carbonyl)-hydrazino]-3-methylcyclopentanone CuCl (0.297 g, 0.1
24 mol) and anhydrous diethyl ether (10 ml) were added. The mixture was cooled to −60 °C under argon and Bu3P
(0.74 ml, 0.124 mol) was added. The yellow solution was cooled to -73 °C and diluted with MeMgCl (Aldrich,
3M in THF, 4.2 ml) was added at such a rate that the internal temperature did not exceed -60°C. cuprat
e) was stirred at -78°C for 20 minutes to form a dark mustard colored solution. To this solution was added cyclopentenone (1.0 ml,
0.0119 mol) was added using a syringe while maintaining the temperature below -70°C. The reaction was allowed to proceed for 1.5 hours at -78°C. Di-t-butyl azodicarboxylate (Fluka, 2.87 ml) in 13 ml anhydrous THF
3 g, 0.0125 mol) was added via cannula over 45 minutes. The resulting dark brown mixture was stirred for 2 hours. The reaction was carried out in 1:9 [NH4OH (conc.):NH4Cl]
(saturated)] and warmed to room temperature overnight. The reaction was diluted with Et2O and the phases were separated. E
The t2O phase was washed with NH4Cl (saturated) and brine,
Dry over Na2SO4, filter and concentrate. The resulting oil was purified by flash chromatography on a 7 cm column using 20% EtOAc/hexanes as eluent. Minimum amount of Et2O in hexane
0.6680 g of a white solid was obtained by recrystallization from . m. p. A second product was also obtained (0.1108 g, m.p.
p. 100-101°C). Mass spectrum (FAB) m/e 329.2 (M+1
) Step B: 2-[N-(1',2'-di-t-butoxy-carbonyl)-hydrazino]-3-methylcyclopentanol 2-[N-(1',2') from Step A above -di-t-butoxycarbonyl)hydrazino]-3-methyl-cyclopentanone (1.1 g, <=0.0034 mol) was dissolved in anhydrous THF under argon and cooled to -78<0>C. L
- Selectride (Aldrich, 1M, 10 ml, 0.01 mol) was added via syringe and the reaction was incubated at -78°C for 4 hours or by TLC (35
% EtOAc/Hexane) until no residual starting material was detected. The reaction was carried out in 10 ml of 1N NaOH solution.
carefully add 10 ml of 30% H2O2
It was stopped by dropping. The solution was allowed to warm to room temperature overnight. The mixture was converted into Et2O (7
5 ml) and the phases were separated. The aqueous phase was converted to Et2O (
2×50 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to give an oil. This oil was diluted with 20% EtOAc.
The resulting white solid was recrystallized from hot Et2O/hexane to give a white amorphous solid. m. p. 146℃ Mass spectrum (FAB) m/e 331.2 (M+1
) Step C: 2-Amino-3-methylcyclopentanol Alcohol obtained in Step B (1.494 g, 0.0048
mol) was dissolved in CH2Cl2 (5 ml) and cooled to -20<0>C. Trifluoroacetic acid (10 ml, 0.048 mol) was added via syringe and the resulting brown mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the brown residual oil was azeotroped with toluene for several hours to give 1.7 g of an oil. Purified hydrazino-methylcyclopentanol (0.5g
) without purification, 4:1 EtOH:HO
Dissolved in Ac (38 ml) and placed in a Parr Shaker flask. To this solution, PtO2 (72 mg) was added and the dark green mixture was hydrogenated at 55-60 psi for 2.5 hours. The solution was filtered through Celite and concentrated. The resulting brown oil was azeotroped with toluene and the residue was diluted with 45:9:1 (C
Purified by flash chromatography using HCl3:MeOH:cNH4OH). The orange solid thus obtained was dissolved in CHCl3/Et2O
(1:5) to obtain a white amorphous solid. m. p. 109-116°C 1H NMR (300 MHz, CDCl3) 3.
92-3.96 (m, 1H), 2.59-2.64
(m, 1H), 2.15(br s, 3H),
1.92 (m, 2H), 1.65 (m, 2H),
1.12 (m, 1H), 1.04 (d, J=6
．． 6Hz, 3H). Step D: N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxy-carbonyl)amino-4(S)-t-butyldimethylsilyloxy-6- Phenyl-2(R)-(4-benzyloxyphenyl)methyl-hexanamide The product of Step C was synthesized with the known 5
(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-t-butyldimethylsilyloxy-2(
Coupled with R)-(4-benzyloxyphenyl)methyl-6-phenylhexanoic acid (EPO337
, 714). Flash chromatography was performed using 25% EtOAc/hexane with an Rf value of 0.2.
The fractions corresponding to (35% EtOAc/hexane) were combined to give 0.50 g of a colorless foam. Step E: N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxy-carbonyl)amino-4(S)-t-butyldimethylsilyloxy-6- Phenyl-2(R)-(4-hydroxyphenyl)methylhexanamide The foamy substance (0.478 g) obtained from Step D was dissolved in THF2.
Dissolved in 0 ml. Palladium hydroxide (0.03g) was added and the reaction was stirred under H2 (balloon) overnight. The solution was filtered through a pad of Celite and evaporated under vacuum to give a white foam (0.4231g). Step F: N-(1-hydroxy-3-methyl-2-cyclo-pentyl)-5(S)-(1,1-dimethylethoxycarbonyl)-amino-4(S)-hydroxy-6-
Phenyl-2(R)-(4-hydroxy-phenyl)-
The product of Methylhexanamide Step E (0.4178 g) was dissolved in 1.75 ml of 1M tetrabutylammonium fluoride in THF and stirred under argon for 24 hours. The mixture was concentrated in vacuo and the residue was chromatographed using 5% MeOH/CHCl3 to give 0.27 g of a white solid. m.
p. 206-208°C Step G: N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonyl)-amino-4(S)-hydroxy-6-phenyl -2(R)-[4-(2-hydroxyethoxy)
-phenyl]methylhexanamide The product of Step F was converted to the title compound by the method of Example 16, Step C. The product was dissolved in 8% MeOH/CHCl
Purified by chromatography at 3°C to give a solid 78m
g, which was triturated with hot EtOAc/hexane to give a white amorphous solid. m. p. 163-165℃

Example 26 N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2
(R)-[4-(2-methoxyethoxy)-phenyl]
- Ethylhexanamide The product from Example 25, Step F (0.05 g) was added to 1-
Methoxy-2-iodoethane (freshly distilled, 0.217
g), and dissolved in dry dioxane (8 ml) containing CsCO3 (0.102 g). The heterogeneous reaction mixture was stirred at 80° C. for 20 hours under argon. The reaction was cooled to room temperature, diluted with CHCl3, and filtered through Celite. The filtrate was concentrated to give a white solid, which was partially purified by column chromatography (5% MeOH/CHCl3). Further preparation of desired product HPLC
Purification and trituration with 1:1 hot EtOAc/hexane gave a white amorphous solid. m. p. 183-185℃

Example 27 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(3-oxabutyloxycarbonylamino)-4(S)-hydroxy-2(R)-((4-(2
-Production of hydroxyethoxy)phenyl)methyl)-6-phenylhexanamide

Step A: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-amino-4(S)-hydroxy-2
Preparation of (R)-((4-(2-hydroxy-ethoxy)phenyl)methyl)-6-phenylhexanamide The product of Example 1 (212 mg) was dissolved in methylene chloride at 0° C.
It was suspended in ml. Trifluoroacetic acid (3 ml) was added and the mixture was stirred for 70 minutes at the same temperature. The solvent was removed under vacuum and the residue was treated with saturated sodium bicarbonate. The resulting solid was separated by filtration and redissolved in methanol. The resulting solution was evaporated to give 136 mg of the title compound. Step B: N-(2-(R)-hydroxy-1(S)-indanyl-5(S)-(3-oxabutyloxycarbonylamino)-4(S)-hydroxy-2(R)-((
4-(2-hydroxyethoxy)phenyl)-methyl-
Production of 6-phenylhexanamide Ethylene glycol monomethyl ether (3.5 equivalents) was mixed with 2.2 m of pyridine.
3.0 equivalents of p-nitrophenyl chloroformate (2.0 g,
27 mmol) was added. When the exothermic reaction subsided, the mixture was filtered and evaporated. Dissolve the residue in ether and add 1
Washed sequentially with 0% citric acid, 10% sodium bicarbonate, and brine. The solution was dried and evaporated to obtain an oil;
This was crushed with hexane and solidified. This solid contained some unreacted p-nitrophenyl chloroformate, which was reacted with triethylamine instead of a pyridine catalyst under the above reaction conditions until the reagent was completely consumed. The pure mixed carbonate thus obtained 1
A 28 mg (0.52 mmol) sample was added to a solution of 66 mg (0.13 mmol) of the product from Step A in THF/DMF. After stirring overnight, the solvent was evaporated and the residue was redissolved in ethyl acetate. This solution was washed with 5% ammonium hydroxide and brine. The solution was dried and evaporated to give a yellow solid. This solid was chromatographed on silica gel (methanol/chloroform) to give the pure title compound. Elemental analysis: Calculated values for C34H42N2O8: C, 67.31; H, 6.98; N, 4.
62 Actual value: C, 67.51; H, 6.63;
N, 4.49

Example 28 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-2(R)-((
4-(2-hydroxy)ethoxyphenyl)methyl-6
- Preparation of Phenylhexanamide The title compound was prepared according to the method of Example 27, except that in Step B, diethylene glycol monomethyl ether was used. Elemental analysis: Calculated value for C36H46N2O9: C, 66.44; H, 7.12; N, 4.
30 Actual value: C, 66.17; H, 6.97;
N, 4.27

Example 29 N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(3,6,9,12-tetraoxatridecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4,7- Production of trioxaoctyl)phenyl]-methylhexanamide
Step A: Preparation of 4-(1,4,7-trioxaoctyl)benzyl-bromide The conversion of 4-hydroxybenzyl alcohol to the title compound is carried out under customary procedures using 1-bromo-3,6-di Alkylation using oxaheptane (sodium hydride/DMF) followed by reaction with carbon tetrabromide and triphenylphosphine. Step B: N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2( R)-[4(1,4,7-trioxaoctyl)
phenyl]-methylhexanamide Example 1, Steps B-D and F to prepare the product of Step A and 5(S)-[1'(S)-(1,1-dimethylethoxycarbonylamino)-2 -phenylethyl]dihydrofuran-2(3H)-one was converted to the title compound. Elemental analysis: Calculated values for C38H50N2O8: C, 68.86; H, 7.60; N, 4.
23 Actual value: C, 68.99; H, 7.54;
N, 4.58 Step C: N-(2(R)-hydroxy-1(S)-indanyl-5(S)-(3,6,9,1
2-tetraoxatridecyloxycarbonylamino)
-4(S)-hydroxy-6-phenyl-2(R)-[
4-(1,4,7-trioxaoctyl)-phenyl]
The product of Step B was converted to the title compound as the hemihydrate by the method of Example 27, except that tetraethylene glycol monomethyl ether was substituted for methylhexanamide ethylene glycol monomethyl ether. Elemental analysis: C43H60N2 O12・0.5 H2O
Calculated value for: C, 65.41; H, 7.
50; N, 3.72 Actual value: C, 65.43;
H, 7.66; N, 3.63

Examples 30-33 The following were prepared by the method of Example 29, substituting the appropriate alcohol and alkylating agent. N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3,
6-dioxaheptyloxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-[4-(
1,4-Dioxapentyl)phenyl]methylhexanamide Elemental analysis: Calculated for C37H48N2O9: C, 66.85; H, 7.28; N, 4.
21 Actual value: C, 67.22; H, 7.25;
N,4.11N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4,7-trio (xaoctyl)phenyl]methylhexanamide Elemental analysis: Calculated for C39H52N2O10: C, 66.08; H, 7.39; N, 3.
95 Actual value: C, 65.69; H, 7.41;
N, 3.81N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(3,6,9-trioxadecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4,7 −
trioxaoctyl)phenyl]methylhexanamide Elemental analysis: Calculated for C41H56N2O11: C, 65.41; H, 7.50; N, 3.
72 Actual value: C, 65.43; H, 7.66;
N, 3.63N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(3,6,9,12-tetraoxatridecyloxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-[4-(
1,4)-Dioxapentyl)phenyl]methylhexanamide (0.32) hydrate elemental analysis: C41H56N2 O11.0.32 H
Calculated value for 2O: C, 64.91; H,
7.53; N, 3.69 Actual value: C, 64.9
0; H, 7.33; N, 3.61

[0097]
Example 34 N-(cis-2(R)-hydroxy-1(S)-indanyl)-5(S)-(2-(2-methoxyethoxy)ethoxycarbonyl)amino-4(S)-hydroxy-6
-Phenyl-2(R)-(4-(3-(2-methoxyethoxy)methoxy)propyl)phenylmethylhexanamide into a 50 ml round bottom flask with a stir bar and argon insertion tube. )-Hydroxy-1(S)-
indanyl)-5(S)-(2-(2-methoxyethoxy)-ethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-(4-(3-hydroxypropyl)phenylmethyl Hexanamide (0.18
0 g, 0.277 mmol), methylene chloride (5.0 m
l), diisopropylethylamine (0.116ml,
0.666 mmol) and 2-methoxyethoxymethyl chloride (0.038 ml, 0.333 mmol) were added. This mixture was stirred at room temperature for 20 hours. 2 more
-Methoxyethoxymethyl chloride (0.020ml)
was added and the mixture was stirred for an additional 7 hours. The reaction was stopped by adding saturated aqueous NaHCO3 and the solvent was removed under vacuum. The aqueous residue was extracted with ethyl acetate,
The combined ethyl acetate extracts were washed with 10% aqueous citric acid, water and brine. Drying (MgSO4), filtration and removal of solvent under vacuum gave the crude product as a crystalline solid. This material was purified using 1:4 ethyl acetate as eluent:
Chromatography on silica gel using hexane. The product was further purified by recrystallization from boiling ethyl acetate-hexane. This gave 0.110 g of the title compound as a microcrystalline solid. m. p.
121-122℃

Examples 35-36 The following were prepared using the method of Example 29 with appropriate modifications. N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(3,6,9-trioxadecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(3,6,9,12-tetra Oxatridecyloxy)phenyl]methylhexanamide Elemental analysis: C45H65N2 O13・0.50 H
Calculated value for 2O: C, 63.59; H,
7.71; N, 3.30 Actual value: C, 63.5
9; H, 7.84; N, 3.30N-(2(R
)-hydroxy-1(S)-indanyl)-5(S)-
(3,6,9,12-tetraoxatridecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(3,6,9,12-tetraoxatridecyl Oxy)phenyl]-methylhexanamide elemental analysis: C47H68N2 O14・0.52 H
Calculated value for 2O: C, 63.12; H,
7.78; N, 3.15 Actual value: C, 63.1
2; H, 7.92; N, 3.11

[0099]
Example 37 N-(2-(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)- (4-(
2-phosphoryloxyethoxy)phenyl)methyl-6
Preparation of -cyclohexyl-hexanamide The title compound was prepared by applying the method of Example 12 to the product of Example 16. Elemental analysis: C35H49Li2N2 O10P・2H2
Calculated value for O: C, 56.91; H, 7
．． 23; N, 3.79 Actual value: C, 56.56
; H, 6.98; N, 3.86

Example 38 HIV Protease Inhibition Assay E. The protease expressed in E.coli and the peptide substrate (Val-Ser-Gln
-Asn-(βnaphthyl)Ala-Pro-Ile-V
The reaction suppression experiment with al 0.5 mg/ml) was carried out at 30°C.
for 1 hour in 50 mM Na acetate pH 5.5. Inhibitors at various temperatures in 1.0 μl DMSO,
Added to 25 μl of peptide solution in water. The reaction is 0.13
0.33 nM protease (0
．． 11 ng) by adding 15 μl. The reaction was stopped with 160 μl of 5% phosphoric acid. The reaction product was analyzed by HPLC (VYDAC wide pore 5 cm C-18 reverse phase,
Separated by acetonitrile gradient, 0.1% phosphoric acid). The degree of inhibition of the reaction was determined from the peak height of the product. HPLC of the individually synthesized products showed quantitative standards and the presence of product composition. Compounds of the invention exhibited IC50 values between about 10 pM and about 10 nM.

While the foregoing specification, together with the examples given for illustrative purposes, indicates the true nature of the invention, practice of the invention may be practiced as coming within the scope of the appended claims and their equivalents. all useful variations, adaptations, modifications,
It is understood to include deletions and additions.

Claims (16)

[Claims] [Claim 1] Structure A-G-B-B-J
I [wherein A is 1) hydrogen 2) R1-C(=O)- {R1 is a) unsubstituted or i) C1-4 alkyl, ii) hydroxy, iii) carboxy, iv) halo (halo is F , Cl, Br or I), v) amino, vi) C1-3 alkoxycarbonyl, vii
) C1-3 alkoxy, viii) -CONR2R3 (R2 and R3 are the same or different, hydrogen, C1-5 alkyl or C1-
5 alkoxyalkyl or joined together directly to form a 5- to 7-membered heterocycle or together with the nitrogen to which they are attached via a heteroatom selected from N, O and S to form a 6-membered heterocycle ), ix) -NR2R3
, x) -N(R)-D-R4 (R is hydrogen or C1-4
is alkyl, and D is -C(=O)-, -C(=S
)-, -S(=O)2-, -C(=NR)-, where R4 is NHR, C1-3 alkyl, C1-4
alkoxy or NR2R3), xi) C3-7 cycloalkyl or C6-10
Aryl, xii) unsubstituted or -OH, N
5- or 6-membered heterocycle substituted with HR or C1-4 alkyl, or xiii) unsubstituted or (a) halo, (b) hydroxy, (c) C1-3 alkoxy, (d) C1-3 alkyl, ( e) -NR2 (R is defined above), (f)
-C(=O)OR, (g) -C(=O)NR2, (h) -SO2NR2, (i) -CH2NR2, (j) -N(R)-C(=O)-R or (k ) −
Aryl with 6 to 10 carbon atoms substituted with one or more of N(R)-SO2R, xiv) X[(CH2)mO]nR (X=CH
2, NR, O, S, SO or SO2, n=1-6,
m is 1 to 3, each within repeating unit n, and R
C1− is substituted with one or more of
6 alkyl b) unsubstituted or i) C1-4 alkyl, ii) C1-3 alkoxy, iii) hydroxy or iv) halo, v) -NR2, vi) -C(=O)OR, vii) -C( =O)NR2, viii) -SO2NR2, ix) -CH2NR2, x) -NRCOR or xi) -NRSO2R, xii) X[(CH2)mO]nR(X=CH2
, NR, O, S, SO or SO2, n=1-6, m is 1-3 but each within repeating unit n, R is defined above)xiii) CH2X[(CH2)
3) R1-SO2-, 4) R1N(R5)-SO2 (R5 is H or C1-
5 alkyl or together with R1 to directly form a 5- to 7-membered heterocycle or to which they are bonded via a heteroatom selected from N, O and S 5) R1N(R5)-C(=O)- 6) R1SC(=O)- 7) R6C(R7)(R8)-O-C(=O)-(R6
, R7 and R8 are independently a) H, b) unsubstituted or i) halo, ii) OH, iii) aryl SO2-, iv) -O-[(CH2)mO]n-R,
c) unsubstituted or i) C1-4 alkyl, ii) C1-3 alkoxy, iii) halo, iv) nitro, v) acetoxy, vi) dimethylaminocarbonyl, vii )
phenyl; viii) aryl substituted with one or more of C1-3 alkoxycarbonyl; d) fluorenyl;
-10 cycloalkyl and can form monocyclic, bicyclic or tricyclic ring systems which can be substituted with C1-4 alkyl. f) is a 5- to 7-membered heterocycle). G is [Formula 1] {Z is O, S or NH. R9a or R9b is independently 1) embedded image or 2) C1-4 alkylene-R11. q is 0-5 and R10 is independently a) hydrogen, b) hydroxy or c) C1-4 alkyl. However, R9a or R9
b is always substituted with R12. R11 is a) C6-C10 aryl unsubstituted or substituted with one or more of R12 and optionally i) halo, ii) C1-4 alkyl, iii) C1-3 alkoxy, b)
contains 1 to 3 heteroatoms selected from N, O, S and may be optionally substituted with one or more of: i) halo; ii) C1-4 alkyl; iii) C1-3 alkoxy; c) unsubstituted or R12 and optionally i)
Hydroxy, ii) C1-4 alkyl, iii) -NH2, -NHR, -NR2,
iv) -NHC(=NH)H, v) -NHC(=NH)-NH2, vi)
-COOH, vii) -C(=O)OR, viii) SR, S(O)R and S(O2)R
, ix) -SO2NHR, x) C1-4 alkylsulfonylamino or arylsulfonylamino, xi) -CONHR, xii) -NHC(=O)R, xiii) -OR, xiv) arylC1-3 alkoxy or xv)
C1-6 alkyl or C1-6 substituted with one or more aryl
6 alkenyl, d) unsubstituted or R12 and optionally i)
Hydroxy, ii) C1-4 alkyl, iii) -NH2, -NHR, -NR2,
iv) -NHC(=NH)H, v) -NHC(=NH)NH2, vi) -COOH, vii) -C(=O)OR, viii) SR, S(O)R and S(O2)R
, ix) -SO2NHR, x) C1-4 alkylsulfonylamino or arylsulfonylamino, xi) -CONHR, xii) -NHC(=O)R, C3-7 cycloalkyl substituted with one or more of the following. R12 is a)X[((CH2)mO)n]R13(X=
CH2, NR, O, S, SO or SO2, n=1~
6, m is 1 to 3, but each is within the repeating unit n, and R13 is i) H or C1-4 alkyl, ii) C(=O)R1, iii) C(=O)X1[(CH2) mO]nR(
X1 is NR or O) iv) P(=O)(
OM)2 (M is a mono- or divalent metal ion) v) C(=O)OR1, vi) R1R5NC(=O)) b) CH2X[((CH2)mO)n]R13 It is. R15 is -H, -C(=O)H, -C1-4-alkyl or -COOR. Q is embedded image (R15 is defined above). X11 is O, S or NH. W is 1) OH, 2) NH2, 3) OR or 4) NHR). }. B is not independently present or [Formula 4] (R20 is a hydrophobic group, a) -CH(CH3)2 b) -CH(CH3)(CH2CH3) or c)-
phenyl). J is 1) YR16 {Y is O or NH. R16 is a) H, b) unsubstituted or i) -NR2, ii) -OR, iii) -NHSO2C1-4 alkyl, iv)
-NHSO2aryl or -NHSO2 (dialkylaminoaryl), v) -CH2OR, vi) -C1-4 alkyl, vii) -C(=O)OR, viii) -C(=O)NR2, ix) -NHC( =NH)NR2 or -NHC
(=N(CN))NR2,x) -NHC(=O)
R, xi) -N(CH2CH2OH)SO2CH3,
xii) -NHC(=O)OCH2Ph, xiii
) -NR3+ A - (A- is a counterion)
xiv) -NR17R18 (R17 and R18 are the same or different, are C1-5 alkyl and are directly bonded together -1 selected from -O-, -S- or -NR-)
xv) aryl, xvi) -CHO, xvii) -OP(O)(ORx)2 (Rx is H or aryl), or xviii) ) amine or quaternary amine or -O-
[(CH2)mO]n-R or -OP(O)(ORx
)2 substituted with one or more of -O-C(=O)C1
C1-6 alkyl substituted with one or more of -4 alkyl, c) -[(CH2)mO]nCH3 or -[(
CH2)mO]nH}2)N(R16)2, 3)-NR17R18 (R17 and R18 are defined above) or 4) {Y, R16 and q are defined above ing. R19 is a) hydrogen, b) unsubstituted or i) halo, ii) -OR (R is H or C1-4 alkyl), iii) -C(=O)OR, iv) -C(=O )NR2, v) -CH2NR2, vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) phenyl, xi) -CF3, xii) -N(R )-SO2R, xiii) -C1-4 alkyl-NR2, xiv
) -OP(O)(ORx)2 (Rx is H or aryl) or xv) amine or quaternary amine or -OP(O
)(ORx)2 substituted with one or more -OC(=O
) aryl substituted with one or more C1-4 alkyls, c) saturated or unsaturated and the ring is unsubstituted, or
i) halo, ii) -OR (R is H, C1-4 alkyl or C1-4 alkenyl), iii) -C(=O)OR, iv) -C(=O)NR2, v) -CH2NR2 , vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) phenyl, xi) -CF3, xii) -N(R)SO2R, xiii) phenyl C1 -4 alkyl, xiv)
-OP(O)(ORx)2 (Rx is H or aryl), xv) amine or quaternary amine or -
OP(O)(ORx)2 or -O[(CH2)mO]
-OC(=O)C1- substituted with one or more of n-R
4 alkyl or xvi) -O-C(=O)-O[(CH2)mO]
5- to 7-membered heterocycle or 7 to 7-membered heterocycle substituted with one or more of n-R
10-membered bicyclic heterocycle d) saturated or unsaturated and unsubstituted on the carbocycle or i) halo, ii) -OR (R is H or C1-4 alkyl), iii) -C( =O)OR, iv) -C(=O)NR2, v) -CH2NR2, vi) -SO2NR2, vii) -NR2, viii) -NHC(=O)R, ix) C1-4 alkyl, x) Phenyl , xi) -CF3, xii) -N(R)SO2R, xiii) -OP(O)(ORx)2 (Rx is H or aryl), xiv) amine or quaternary amine, -OP(O) (ORx)2 or -O-[(C
-OC(=
O) C1-4 alkyl or xv) -O-C(=O)-O-[(CH2)mO
] n-R 5- to 7-membered carbon ring or 7 substituted with one or more
~10-membered bicyclic carbocycle. }. ] or a pharmaceutically usable salt thereof. [Claim 2] A is R1C(=O)- or R6C(R7)(R8)OC
The compound according to claim 1, wherein (=O)- and G is [Image Omitted]. [Claim 3] B does not exist or one B exists, and Q
3. The compound according to claim 2, wherein is -C(OH)H-CH2. 4. A compound according to claim 3, wherein B is absent, J is NHR19 and R19 is a substituted 7- to 10-membered bicyclic carbocycle or heterocycle, which is saturated or unsaturated. 5. The compound according to claim 4, wherein J is indanyl, benzo[C]thiopyranyl-2,2-dioxide or cyclopentyl, all of which are unsubstituted or substituted. [Claim 6] N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-
2(R)-(4-(1,4,7-trioxaoctyl)
phenyl)methyl-6-phenylhexanamide, N-
(2(R)-hydroxy-1(S)-indanyl)-5
(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-
4-(2-hydroxyethoxy)phenylmethylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S )-Hydroxy-6-phenyl-2(R)-4-(2-hydroxyethyl)phenylmethylhexanamide, N-(2(R)-hydroxy-
1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2(R)-4-(3-hydroxypropyl)phenylmethyl Hexanamide, N-(2(R)
-hydroxy-1(S)-indanyl)-5(S)-(
1,1-dimethylethoxycarbonyl)amino-4(S
)-hydroxy-6-phenyl-2(R)-4-(3-
(2-Methoxyethoxy)methoxypropyl)phenylmethylhexanamide, [5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-4-( 2-Hydroxyethoxy)phenylmethylhexanoyl]-valine-N-3
, 6,9,12-tetraoxatridecylamide, [5
(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-
4-(2-hydroxyethoxy)phenylmethylhexanoyl]-valine-N-3,6,9,12,15-pentaoxapentadecylamide, N-(2(R)-hydroxy-1(S)-indanyl) )-5(S)-(1,1-
dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4,7
,10-tetraoxaundecyl))phenyl]methylhexanamide, N-(2(R)-(hydroxy-1(
S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6
-Phenyl-2(R)-[4-(methoxyethoxyethoxy)phenyl]methylhexanamide, N-(2(R)
)-hydroxy-1(S)-indanyl)-5(S)-
(1,1-dimethylethoxycarbonylamino)-4(
S)-hydroxy-6-phenyl-2(R)-[4-(
methoxyethoxy)phenyl]methylhexanamide,
N-(2(R)-hydroxy-1(S)-indanyl)
-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R
)-[4-(1,4,7,10,13-pentaoxatetradecyl)phenyl]methylhexanamide, N-(
4-(3,4-dihydro-(1H)-benzo[C]thiopyranyl-2,2-dioxide))-5(S)-(1,
1-dimethylethoxycarbonylamino)-4(S)-
Hydroxy-6-phenyl-2(R)-4(3-hydroxypropyl)phenylmethylhexanamide, N-(
2(R)-hydroxy-1(S)-indanyl)-5(
S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(5-thia-
7-hydroxy-2(E)-hepten-1-yl)-6
-Phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R )-(5-thia-8-hydroxy-2
(E)-octen-1-yl)-6-phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino) )-4(S)-hydroxy-2(R)
-4-(4-hydroxy-2-thiabut-1-yl)phenylmethyl-6-phenylhexanamide, N-(2
(R)-hydroxy-1(S)-indanyl)-5(S
)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(5,8,11
, 14,17-pentaoxaoctadec-2(E)-en-1-yl)-6-phenylhexanamide, N-(
2(R)-hydroxy-1(S)-indanyl)-5(
S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-4-(2-hydroxyethylsulfonylmethyl)phenylmethyl-6
-Phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R )-4-(2,5,8,11,14-
Pentaoxapentadec-1-yl)phenylmethyl-
6-phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-
dimethylethyloxycarbonylamino)-4(S)-
Hydroxy-2(R)-(4-(2-(hydroxy)ethoxy)phenyl)methyl-6-cyclohexyl-hexanamide, N-(4-fluoro-2(R)-hydroxy-1(S)-indanyl) -5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2-hydroxyethyloxy)phenylmethyl-6-phenylhexanamide,
N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonyl)amino-4(S)-hydroxy-6-phenyl-2
(R)-[4-(2-hydroxyethoxy)phenyl]
Methylhexanamide, N-(1-hydroxy-3-methyl-2-cyclopentyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R )-[4-(2-methoxyethoxy)phenyl]methylhexanamide, N-(2
(R)-hydroxy-1(S)-indanyl)-5(S
)-(1,1-dimethylethoxycarbonylamino)-
4(S)-hydroxy-6-phenyl-2(R)-[4
-(1,4,6,9,12,15,18-heptaoxa-5-oxo-nonadecyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5( S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(6-aza-1,4,9,12,1
5,18-hexaoxa-5-oxa-nonadecyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1
-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(2-phosphoryloxyethoxy)phenyl]methylhexanamide or N-(2(R)-hydroxy-1 (S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-6-phenyl-
2(R)-[4-(2-phosphoryloxypropyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3-oxabutyloxy carbonylamino)-4(S)-hydroxy-2(R)-(4-(2-hydroxy)ethoxyphenyl)methyl-6-phenylhexanamide, N-
(2(R)-hydroxy-1(S)-indanyl)-5
(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-2(R)-((4-
(2-hydroxy)ethoxy)phenyl)methyl-6-
Phenylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3,6,9,
12-Tetraoxatridecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-
[4-(1,4,7-trioxaoctyl)phenyl]
Methylhexanamide, N-(2(R)-hydroxy-
1(S)-indanyl)-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(1,4- dioxapentyl)phenyl]methylhexanamide, N
-(2(R)-hydroxy-1(S)-indanyl)-
5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2
(R)-[4-(1,4,7-trioxaoctyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3, 6
,9-trioxadecyloxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-[4-
(1,4,7-trioxaoctyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(3,6,9,12-tetraoxa-tridecyloxycarbonylamino)-4
(S)-hydroxy-6-phenyl-2(R)-[4-
(1,4-Dioxapentyl)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(2-(2-methoxyethoxy)ethoxycarbonylamino) )-4(S)-hydroxy-2(R)-(4-(3-(2-methoxyethoxy)methoxy)propyl)phenylmethyl-6-phenylhexanamide, N-(2(R)-hydroxy-1 (S)-
indanyl)-5(S)-(3,6,9-trioxadecyloxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-[4-(3,6,9,12
-tetraoxatridecyloxy)phenyl]methylhexanamide, N-(2(R)-hydroxy-1(S)
-indanyl)-5(S)-(3,6,9,12-tetraoxatridecyloxycarbonylamino)-4(S
)-hydroxy-6-phenyl-2(R)-[4-(3
,6,9,12-tetraoxatridecyloxy)phenyl]methylhexanamide, N-(2-(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1
-dimethylethoxycarbonylamino)-4(S)-hydroxy-2(R)-(4-(2-phosphoryloxyethoxy)phenyl)methyl-6-cyclohexylhexanamide, or a pharmaceutically usable salt thereof. Compound. [Claim 7] N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-
7. The compound according to claim 6, which is 2(R)-(4-(2-(hydroxy)ethoxy)phenyl)methyl-6-cyclohexylhexanamide or a pharmaceutically usable salt thereof. [Claim 8] N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-
2(R)-(4-(1,4,7-trioxaoctyl)
7. The compound according to claim 6, which is phenyl)methyl-6-phenylhexanamide or a pharmaceutically usable salt thereof. Claim 9: N-(2(R)-hydroxy-1(S
)-indanyl)-5(S)-(1,1-dimethylethyloxycarbonylamino)-4(S)-hydroxy-
7. The compound according to claim 6, which is 2(R)-(4-(2-(hydroxy)-ethoxy)phenyl)methyl-6-phenylhexanamide or a pharmaceutically usable salt thereof. 10. Compound N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(3,6-dioxaheptyloxycarbonylamino)-4(S)-hydroxy-2 (R)-((4-(2-hydroxy)ethoxy)phenyl)methyl-6-phenylhexanamide or a pharmaceutically usable salt thereof. 11. Compound N-(2(R)-hydroxy-1(S)-indanyl)-5(S)-(2-(2-methoxyethoxy)ethoxycarbonylamino)-4(S
)-Hydroxy-2(R)-(4-(3-(2-methoxyethoxy)methoxy)propyl)phenylmethyl-6
- Phenylhexanamide or a pharmaceutically usable salt thereof. 12. Compound N-(2-(R)-hydroxy-1(S)-indanyl)-5(S)-(1,1-dimethylethoxycarbonylamino)-4(S)-hydroxy-2( R)-(4-(2-phosphoryloxyethoxy)phenyl)methyl-6-cyclohexylhexanamide or a pharmaceutically usable salt thereof. 13. A pharmaceutical composition useful for inhibiting HIV protease, comprising an effective amount of a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. 14. A pharmaceutical composition useful for the prevention or treatment of HIV infection or the treatment of AIDS or ARC, comprising an effective amount of a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. . 15. HI, characterized in that an effective amount of the compound according to any one of claims 1 to 12 is administered to a mammal.
Method for inhibiting V protease. 16. HI, characterized in that an effective amount of the compound according to any one of claims 1 to 12 is administered to a mammal.
Prevention of V infection or treatment of HIV infection or AIDS or AR
Treatment method for C.